Synthesis of enantiomerically pure amino-substituted fused bicyclic rings

ABSTRACT

This invention describes various processes for synthesis and resolution of racemic amino-substituted fused bicyclic ring systems. One process utilizes selective hydrogenation of an amino-substituted fused bicyclic aromatic ring system. An alternative process prepares the racemic amino-substituted fused bicyclic ring system via nitrosation. In addition, the present invention describes the enzymatic resolution of a racemic mixture to produce the (R)- and (S)-forms of amino-substituted fused bicyclic rings as well as a racemization process to recycle the unpreferred enantioner. Further provided by this invention is an asymmetric synthesis of the (R)- or (S)-enantiomer of primary amino-substituted fused bicyclic ring systems.

This application claims benefit of priority to U.S. Provisional PatentApplication No. 60/323,201, filed Sep. 12, 2001, which is herebyincorporated by reference as if fully set forth.

TECHNICAL FIELD

This invention describes various processes for synthesis and resolutionof racemic amino-substituted fused bicyclic ring systems, in particular,amino-substituted tetrahydroquinolines or tetrahydroisoquinolines. Oneprocess utilizes selective hydrogenation of an amino-substituted fusedbicyclic ring. An alternative process prepares a racemicamino-substituted fused bicyclic ring system via nitrosation. Inaddition, the present invention describes the enzymatic resolution of aracemic mixture to produce the (R)- and (S)-forms of amino-substitutedfused bicyclic ring systems, such as amino-substituted5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline. Anotheraspect of the invention describes a process to racemize theenantiomerically enriched (R)- and (S)-forms of amino-substituted fusedbicyclic ring systems. Further provided by this invention is anasymmetric synthesis of an amino-substituted fused bicyclic ring toproduce the desired enantiomer.

BACKGROUND OF THE INVENTION

It is desired by those of skill in the art to produce enantiomeric formsof pharmaceutical compounds, since such enantiomers often have increasedactivity for selected diseases when compared with the racemic form ofthe same compound. For example, 8-amino-5,6,7,8-tetrahydroquinolines areutilized as intermediates in the preparation of novel heterocycliccompounds that bind to chemokine receptors and demonstrate protectiveeffects against infection of target cells by human immunodeficiencyvirus (HIV). See WO 00/56729.

Approximately 40 human chemokines have been described, that function, atleast in part, by modulating a complex and overlapping set of biologicalactivities important for the movement of lymphoid cells andextravasation and tissue infiltration of leukocytes in response toinciting agents (See, for example: P. Ponath, Exp. Opin. Invest. Drugs,7:1-18, 1998). These chemotactic cytokines, or chemokines, constitute afamily of proteins, approximately 8-10 kDa in size. Chemokines appear toshare a common structural motif, that consists of 4 conserved cysteinesinvolved in maintaining tertiary structure. There are two majorsubfamilies of chemokines: the “CC” or β-chemokines and the “CXC” orα-chemokines. The receptors of these chemokines are classified basedupon the chemokine that constitutes the receptor's natural ligand.Receptors of the β-chemokines are designated, “CCR”; while those of theα-chemokines are designated “CXCR”.

Chemokines are considered to be principal mediators in the initiationand maintenance of inflammation. More specifically, chemokines have beenfound to play an important role in the regulation of endothelial cellfunction, including proliferation, migration and differentiation duringangiogenesis and re-endothelialization after injury (Gupta et al., J.Biolog. Chem., 7:4282-4287, 1998). Two specific chemokines have beenimplicated in the etiology of infection by human immunodeficiency virus(HIV).

For example, U.S. Pat. Nos. 5,583,131, 5,698,546 and 5,817,807 disclosecyclic compounds that are active against HIV-1 and HIV-2. Thesecompounds exhibit anti-HIV activity by binding to the chemokine receptorCXCR4 expressed on the surface of certain cells of the immune system.This competitive binding thereby protects these target cells frominfection by HIV which utilizes the CXCR-4 receptor for entry. Inaddition, these compounds antagonize the binding, signaling andchemotactic effects of the natural CXC-chemokine for CXCR-4, stromalcell-derived factor 1 α (SDF-1).

Additionally cyclic polyamine antiviral agents described in theabove-mentioned patents have the effect of enhancing production of whiteblood cells as well as exhibiting antiviral properties. See U.S. Pat.No. 6,365,583. Thus, these agents are useful for controlling theside-effects of chemotherapy, enhancing the success of bone marrowtransplantation, enhancing wound healing and burn treatment, as well ascombating bacterial infections in leukemia.

Therefore, a skilled artisan would be interested in more effective andefficient processes for producing racemates and enantiomers of variousring systems. This invention provides such processes.

SUMMARY OF THE INVENTION

The invention provides a process for synthesizing a racemicamino-substituted 5,6,7,8-tetrahydroquinoline or a racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline comprising:

a) reacting an amino-substituted quinoline of the formula I or anamino-substituted isoquinoline of the formula II with anamine-protecting group compound in an organic solvent to produce anamine-protected, substituted quinoline or isoquinoline:

b) hydrogenating the amine-protected, substituted quinoline orisoquinoline in a strongly acidic solvent at an elevated temperature toform the 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;and

c) hydrolyzing the amine-protecting group to produce the desired racemicamino-substituted 5,6,7,8-tetrahydroquinoline or racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline;

wherein NH₂ is located at any position on the benzene portion of thequinoline or isoquinoline, R¹ is located at any other hydrogen positionon the quinoline or isoquinoline ring; m is 0-4; and wherein R¹ isselected from the group consisting of nitro, cyano, carboxylic acid,alkyl, alkoxy, cycloalkyl, a protected hydroxyl, a protected thiol, aprotected amino, acyl, carboxylate, carboxamide, sulfonamide, anaromatic group and a heterocyclic group.

The invention also provides a process for synthesizing a racemicamino-substituted 5,6,7,8-tetrahydroquinoline or a racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline comprising:

a) reacting either a substituted 5,6,7,8-tetrahydroquinoline of theformula III or a substituted 5,6,7,8-tetrahydroisoquinoline of theformula IV

with at least 2 equivalents of an alkyllithium base, or a lithium,sodium, or potassium amide base, and then with a nitrosating agent toform an oxime; and

b) reducing the oxime to produce the racemic amino-substituted5,6,7,8-tetrahydroquinoline or the racemic amino-substituted5,6,7,8-tetrahydroisoquinoline;

wherein the amino is located at the 8-position on the quinoline or the5-position on the isoquinoline; R² is located at any other hydrogenposition on the quinoline or isoquinoline ring; m is 0-4; and wherein R²is selected from the group consisting of halo, nitro, cyano, a protectedcarboxylic acid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, aprotected thiol, a protected amino, acyl, carboxylate, carboxamide,sulfonamide, an aromatic group and a heterocyclic group.

Further provided is a process for synthesizing a keto-substituted5,6,7,8-tetrahydroquinoline or a keto-substituted5,6,7,8-tetrahydroisoquinoline comprising:

a) reacting either a substituted 5,6,7,8 tetrahydroquinoline of theformula III or a substituted 5,6,7,8-tetrahydroisoquinoline of theformula IV

with at least 2 equivalents of an alkyllithium base, or a lithium,sodium, or potassium amide base; and then with a nitrosating agent toform an oxime; and

b) hydrolyzing the oxime to produce the corresponding ketone;

wherein the keto is located at the 8-position on the quinoline or the5-position on the isoquinoline; R² is located at any other hydrogenposition on the quinoline or isoquinoline; m is 0-4; and R² is selectedfrom the group consisting of halo, nitro, cyano, a protected carboxylicacid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, a protectedthiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide,an aromatic group, and a heterocyclic group.

Also, this invention provides a process for resolving racemicamino-substituted 5,6,7,8-tetrahydroquinoline of the formula V orracemic amino-substituted 5,6,7,8-tetrahydroisoquinoline of the formulaVI to produce the two enantiomers,

comprising:

a) enantioselectively acylating or carbamoylating the racemicamino-substituted 5,6,7,8-tetrahydroquinoline or the racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline using anenantioselective enzyme as a catalyst; and

b) separating the unreacted amino-substituted5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline as thefirst enantiomer, from the enantiomeric amide- or carbamate-substituted5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline; and

c) cleaving the amide or carbamate group to isolate the secondenantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or5,6,7,8-tetrahydroisoquinoline;

wherein NH₂ is located at any position on the saturated portion of thequinoline or isoquinoline; R² is located at any other hydrogen positionon the quinoline or isoquinoline ring; m is 0-4; and R² is selected fromthe group consisting of halo, nitro, cyano, carboxylic acid, alkyl,alkenyl, cycloalkyl, hydroxyl, thio, a protected amino, acyl,carboxylate, carboxamide, sulfonamide, an aromatic group and aheterocyclic group.

Another process is provided for resolving racemic amino-substituted5,6,7,8-tetrahydroquinoline of the formula V or amino-substituted5,6,7,8-tetrahydroisoquinoline of the formula VI to produce one of theenantiomers,

comprising:

a) enantioselectively acylating or carbamoylating the racemicamino-substituted 5,6,7,8-tetrahydroquinoline or the racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline using anenantioselective enzyme as a catalyst to produce a mixture of thecorresponding unreacted amine in the first enantiomeric form and thereacted amide or carbamate in the second enantiomeric form; and

b) isolating the first enantiomer of the amino-substituted5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;

wherein NH₂ is located at any position on the saturated portion of thequinoline or isoquinoline; R² is located at any other hydrogen positionon the quinoline or isoquinoline ring; m is 0-4; and R² is selected fromthe group consisting of halo, nitro, cyano, carboxylic acid, alkyl,alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl,carboxylate, carboxamide, sulfonamide, an aromatic group and aheterocyclic group.

A process is provided for resolving racemic amino-substituted5,6,7,8-tetrahydroquinoline or racemic amino-substituted5,6,7,8-tetrahydroisoquinoline to produce the two enantiomers,comprising:

a) reacting racemic amide-or carbamate-substituted5,6,7,8-tetrahydroquinoline of the formula VII or racemic amide-orcarbamate-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VIII

with water, an alcohol, or a primary or secondary amine using anenantioselective enzyme as a catalyst to produce a mixture of thecorresponding amine in the first enantiomeric form, and the unreactedamide or carbamate in the second enantiomeric form;

b) separating the first enantiomer of the amino-substituted5,6,7,8-tetrahydroquinoline or amino-substituted5,6,7,8-tetrahydroisoquinoline, from the unreacted amide or carbamate;and

c) cleaving the amide or carbamate group to produce the secondenantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline oramino-substituted 5,6,7,8-isoquinoline;

wherein the amide or carbamate group is located at any position on thesaturated portion of the quinoline or isoquinoline; R² is located at anyother hydrogen position on the quinoline or isoquinoline ring; m is 0-4;R² is selected from the group consisting of halo, nitro, cyano,carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, aprotected amino, acyl, carboxylate, carboxamide, sulfonamide, anaromatic group and a heterocyclic group; and R³ is an optionallysubstituted carbon atom or an optionally substituted oxygen atom.

Additionally, this invention provides a process for resolving racemicamino-substituted 5,6,7,8-tetrahydroquinoline or racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline to produce one of theenantiomers, comprising:

a) reacting racemic amide-or carbamate-substituted5,6,7,8-tetrahydroquinoline of the formula VII or racemic amide-orcarbamate-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VIII

with water, an alcohol, or a primary or secondary amine using anenantioselective enzyme as a catalyst to produce a mixture of thecorresponding amine in the first enantiomeric form, and the unreactedamide or carbamate in the second enantiomeric form; and

b) isolating the first enantiomer of the amino-substituted5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;

wherein the amide or carbamate is located at any position on thesaturated portion of the quinoline or isoquinoline; R² is located at anyother hydrogen position on the quinoline or isoquinoline ring; m is 0-4;R² is selected from the group consisting of halo, nitro, cyano,carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, aprotected amino, acyl, carboxylate, carboxamide, sulfonamide, anaromatic group and a heterocyclic group; and R³ is an optionallysubstituted carbon atom or an optionally substituted oxygen atom.

A process is provided for racemizing an enantiomerically enrichedamino-substituted 5,6,7,8-tetrahydroquinoline of the formula XIII oramino-substituted 5,6,7,8-tetrahydroisoquinoline of the formula XIV toproduce the corresponding racemic mixture:

comprising:

a) heating the enantiomerically enriched amino-substituted5,6,7,8-tetrahydroquinoline or amino-substituted5,6,7,8-tetrahydroisoquinoline neat or in an organic solvent in thepresence or absence of an additive; and

b) when either R⁷ or R⁸ is not hydrogen, cleaving the R⁷ or R⁸ groupunder conditions to form the corresponding amino;

wherein NR⁷R⁸ is located at any position on the saturated portion of thequinoline or isoquinoline; R² is located at any other hydrogen positionon the quinoline or isoquinoline ring; m is 0-4;

R² is selected from the group consisting of halo, nitro, cyano,carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thio, a protectedamino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group,and a heterocyclic group; and

R⁷ and R⁸ are each selected from the group consisting of hydrogen,alkyl, aryl, heteroalkyl, heteroaryl, aralkyl, alkanoyl, alkylsulfonyl,a carbonyl- or sulfonyl-group substituted by an aromatic or heterocyclicring, aryloxycarbonyl, alkoxycarbonyl, arylcarbamoyl, alkylcarbamoyl,arylthiocarbonyl, alkylthiocarbonyl, and carbamoyl.

A process is provided for synthesizing an enantiomer of a primaryamino-substituted fused bicyclic ring of formula IX comprising:

a) forming the Schiff base of a keto group located on ring B of thefused bicyclic ring by reacting it with an enantiomerically-pure primaryamine chiral auxiliary R*NH₂ of the formula X

 to produce the corresponding enantiomerically-pure imine of the fusedbicyclic ring;

b) diastereoselectively reducing the imine to produce the correspondingenantiomerically-pure secondary amine on the fused bicyclic ring; and

c) removing the chiral auxiliary R* to form the enantiomer of theprimary amino-substituted fused bicyclic ring;

wherein ring A is a heteroaromatic 5- or 6-membered ring, P is anitrogen atom, sulfur atom or oxygen atom; ring B is a 5- or 6-memberedcycloalkyl or heterocycloalkyl;

wherein NH₂ is located at a position on ring B; and R² is located at anyother hydrogen position on the fused bicyclic ring;

wherein m is 0-4; R² is selected from the group consisting of halo,nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl,thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide,an aromatic group and a heterocyclic group; and

R⁴, R⁵, and R⁶ are each different and selected from the group consistingof hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, and a 5- or6-membered aromatic ring; and at least one of R⁴, R⁵, or R⁶ is a 5- or6-membered aromatic ring.

DETAILED DESCRIPTION OF THE INVENTION

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes R and S are used to denotethe absolute configuration of the molecule about its chiral center(s).The prefixes “d” and “l” or (+) and (−) are employed to designate thesign of rotation of plane-polarized light by the compound, with (−) or“1” meaning that the compound is “levorotatory” and with (+) or “d”meaning that the compound is “dextrorotatory”. There is no correlationbetween the nomenclature for the absolute stereochemistry and for therotation of an enantiomer. For a given chemical structure, thesecompounds, called “stereoisomers”, are identical except that they aremirror images of one another. A specific stereoisomer can be referred toas an “enantiomer” and a mixture of such isomers is often called an“enantiomeric” or “racemic” mixture. See e.g., Streitwiesser, A. &Heathcock, C. H., Introduction to Organic Chemistry, 2nd Edition,Chapter 7 (MacMillan Publishing Co., USA, 1981). In the presentapplication, the designation (R,S) represents the racemic mixture of theR- and S-enantiomers and the individual enantiomers also can bedesignated as, for example, (8R)- and/or(8S)-amino-5,6,7,8-tetrahydroquinoline.

“Enantiomerically pure” or “enantiomerically enriched” or “opticallypure” or “substantially optically pure” or “enantiopure” as used hereinmeans that the enantiomer or isomer is substantially free of thealternative enantiomer or isomer, wherein the composition is at least90% by weight of the desired isomer and 10% by weight or less of thealternate isomer. In a more preferred embodiment, the terms mean thatthe composition is at least 99% by weight of the desired isomer and 1%by weight or less of the alternative isomer or enantiomer. Thesepercentages are based upon the total amount of compound in thecomposition.

The term “enantiomeric excess” or “ee” is related to the term “opticalpurity” in that both are measures of the same phenomenon. The value ofee will be a number from 0 to 100, 0 being racemic and 100 being pure,single enantiomer. A compound that is referred to as 98% optically purecan be described as 98% ee. See, e.g., March J., Advanced OrganicChemistry: Reactions, Mechanisms and Structures, 3rd Edition, Chapter 4(John Wiley & Sons, USA, 1985). The percent optical purity for a givensample is defined as:${{Percent}\quad {optical}\quad {purity}} = {\frac{\lbrack\alpha\rbrack {obs}}{\lbrack\alpha\rbrack \max} \times 100}$

Where [α] obs is the observed angle of rotation of plan-polarized lightand [α] max is the maximum rotation possible (i.e., the rotation thatwould be observed for an enantiomerically pure sample). Assuming thatthere is a linear relationship between [α] and concentration, then theoptical purity is equal to the percent excess of one enantiomer over theother: $\begin{matrix}{{{optical}\quad {purity}} = {{e{nantiomeric}}\quad {excess}\quad ({ee})}} \\{= {\frac{\lbrack R\rbrack - \lbrack S\rbrack}{\lbrack R\rbrack + \lbrack S\rbrack} \times 100}} \\{= {{\% R} - {\% {S.}}}}\end{matrix}$

The substituent groups defined below can be optionally substituted;therefore, for example, when the term “alkyl” is utilized, it alsoencompasses substituted alkyls.

General structures are defined as follows: wherein, ring A or ring C isan optionally substituted heteroaromatic 5- or 6-membered ring, and P isan optionally substituted carbon atom, an optionally substitutednitrogen atom, sulfur or oxygen atom. Ring B or ring D is an optionallysubstituted saturated or partially saturated carbon 5- to 6-memberedcycloalkyl or heterocycloalkyl.

Examples of the optionally substituted 5- or 6-membered ring A or ring Care pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole,pyrazole, triazole, oxazole, thiazole. Six-membered rings are preferredfor ring A or ring C, particularly pyridine.

Examples of the optionally substituted ring B or ring D are cyclohexane,piperidine, piperazine, hexahydropyridazine, tetrahydrofuran,tetrahydrothiophene, tetrahydropyran, and tetrahydrothiapyran, with thepreferred combination of rings A and B, or C and D, being5,6,7,8-tertrahydroquinoline and 5,6,7,8-tetrahydroisoquinoline.

In the above examples, the “optional substituents” in Rings A, B, C, andD may be nitro, canyo, carboxylic acid, an optionally substituted alkylor cycloalkyl groups, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally substituted amino oracyl group, an optionally substituted carboxylate, carboxamide orsulfonamide group, an optionally substituted aromatic or heterocyclicgroup.

Examples of the optionally substituted alkyl include C₁₋₁₂ alkyl,including methyl, ethyl, propyl etc. and examples of the optionallysubstituted cycloalkyl groups include C₃₋₁₀ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Inthese cases, C₁₋₆ alkyl and cycloalkyl are preferred. The optionalsubstituent may also be an optionally substituted aralkyl (e.g. phenylC₁₋₄ alkyl) or heteroalkyl for example, phenylmethyl (benzyl),phenethyl, pyridinylmethyl, pyridinylethyl etc. The heterocyclic groupmay be a 5- or 6-membered ring containing 1-4 heteroatoms.

Examples of the optionally substituted hydroxyl and thiol groups includean optionally substituted alkyl (e.g. C₁₋₁₀ alkyl) such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyletc., preferably (C₁₋₆) alkyl; an optionally substituted cycloalkyl(e.g. C₃₋₇ cycloalkyl, etc. such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc.); an optionally substitutedaralkyl (e.g. phenyl-C₁₋₄ alkyl, e.g. benzyl, phenethyl, etc.). Wherethere are two adjacent hydroxyl or thiol substituents, the heteroatomsmay be connected via an alkyl group such as O(CH₂)_(n)O and S(CH₂)_(n)S(where n=1-5). Examples include methylenedioxy, ethylenedioxy etc.Oxides of thio-ether groups such as sulfoxides and sulfones are alsoencompassed.

Further examples of the optionally substituted hydroxyl group include anoptionally substituted C₂₋₄ alkanoyl (e.g. acetyl, propionyl, butyryl,isobutyryl, etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl,ethanesulfonyl, etc.) and an optionally substituted aromatic andheterocyclic carbonyl group including benzoyl, pyridinecarbonyl etc.

The substituents on the optionally substituted amino group may bind toeach other to form a cyclic amino group (e.g. 5- to 6-membered cyclicamino, etc. such as tetrahydropyrrole, piperazine, piperidine,pyrrolidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). Saidcyclic amino group may have a substituent, and examples of thesubstituents include halogen (e.g. fluorine, chlorine, bromine, iodine,etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxylgroup, an optionally halogenated C₁₋₄ alkyl (e.g. trifluoromethyl,methyl, ethyl, etc.), an optionally halogenated C₁₋₄ alkoxy (e.g.methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C₂₋₄ alkanoyl(e.g. acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.) the number of preferredsubstituents are 1 to 3.

The amino group may also be substituted once or twice (to form asecondary or tertiary amine) with a group such as an optionallysubstituted alkyl group including C₁₋₁₀ alkyl (e.g. methyl, ethyl propyletc.) or an optionally substituted cycloalkyl group such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In these cases,C₁₋₆ alkyl and cycloalkyl are preferred. The amine group may also beoptionally substituted with an aromatic or heterocyclic group, aralkyl(e.g. phenyl C₁₋₄ alkyl) or heteroalkyl for example, phenyl, pyridine,phenylmethyl (benzyl), phenethyl, pyridinylmethyl, pyridinylethyl etc.The heterocyclic group may be a 5- or 6-membered ring containing 1-4heteroatoms. The optional substituents of the “optionally substitutedamino groups” are the same as defined above for the “optionallysubstituted cyclic amino group.”

The amino group may be substituted with an optionally substituted C₂₋₄alkanoyl e.g. acetyl, propionyl, butyryl, isobutyryl etc., or a C₁₋₄alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.) or a carbonylor sulfonyl substituted aromatic or heterocyclic ring, e.g.benzenesulfonyl, benzoyl, pyridinesulfonyl, pyridinecarbonyl etc. Theheterocycles are as defined above. The optional substituents on theamine substituents described above are the same as defined above for the“optionally substituted cyclic amino group.”

Examples of the optionally substituted acyl group as the substituents onthe rings A, B, C, and D include a carbonyl group or a sulfonyl groupbinding to hydrogen; an optionally substituted alkyl (e.g. C₁₋₁₀ alkylsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl, etc.; an optionallysubstituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc., such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); an optionallysubstituted 5- to 6-membered monocyclic aromatic group (e.g. phenyl,pyridyl, etc.).

Examples of the optionally substituted carboxylate group (ester groups)include an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl, etc.); an optionallysubstituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc. such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); an optionallysubstituted aryl (e.g. phenyl, naphthyl, etc.) and C₁₋₄ aryl forexample, benzyl, phenethyl etc. Groups such as methoxymethyl,methoxyethyl etc., are also encompassed.

Examples of the optionally substituted carboxamide and sulfonamidegroups are identical in terms of the amine definition as the “optionallysubstituted amino group” defined above.

Examples of the optionally substituted aromatic or heterocyclic groupsas substituents for Rings A, B, C, and D are phenyl, naphthyl, or a 5-or 6-membered heterocyclic ring containing 1-4 heteroatoms. The optionalsubstituents are essentially identical to those listed above for RingsA, B, C, and D.

In the above examples the number of substituents on Rings A, B, C, and Dmay be 1-4 preferably 1-2. The substituents on the optionallysubstituted groups are the same as the optionally substituted groupsdescribed above. Preferred substituents are halogen (fluorine, chlorineetc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxylgroup, carboxylate group, sulfonate group, sulfonamide group,carboxamide group, an optionally halogenated C₁₋₄ alkoxy (e.g.trifluoromethoxy, etc.), C₂₋₄ alkanoyl (e.g. acetyl, propionyl, etc.) oraroyl, a C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl,etc.), an optionally substituted aryl or heterocyclic group. The numberof substituents on the said groups are preferably 1 to 3.

The preferred substituent for rings A, B, C, and D is an amino groupsubstituted with an optionally substituted C₂₋₄ alkanoyl e.g. acetyl,propionyl, butyryl, isobutyryl etc., or a C₁₋₄ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.) or a carbonyl or sulfonylsubstituted aromatic or heterocyclic ring; most preferable is anacetyl-substituted amino group.

For the amide substituent, examples include an optionally substitutedalkyl (e.g. C₁₋₁₀ alkyl such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,heptyl, octyl, nonyl, decyl, etc., preferably lower (C₁₋₆) alkyl, etc.;an optionally substituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc., suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);an optionally substituted 5- to 6-membered monocyclic aromatic group(e.g. phenyl, pyridyl, etc.). The optional substituents may also be anoptionally substituted aralkyl (e.g. phenyl C₁₋₄ alkyl) or heteroalkylfor example, phenylmethyl (benzyl), phenethyl, pyridinylmethyl,pyridinylethyl etc. The heterocyclic group may be a 5- or 6-memberedring containing 1-4 heteroatoms. Optional substituents also includehalogens (fluorine, chlorine, bromine, etc.) and optionally substitutedheteroatoms such as oxygen, sulfur, nitrogen, etc.

Amine groups can be protected from reactivity during a particular partof a process by groups such as acyls, carbamates, enamines, orsulfonamides, and the like. Hydroxyls can be protected via ketones,esters or ethers; carboxylic acids and thiols can be protected by estersor ethers.

The present invention describes various methods for synthesizing andresolving the enantiomeric forms of amino-substituted bicyclic fusedring systems as described below. Selective Hydrogenation Process

This invention provides for the selective hydrogenation of a fusedbicyclic ring system. The system comprises an optionally-substituted 5-or 6-membered heteroaromatic ring fused to an optionally-substituted 5-or 6-membered heteroaromatic or aromatic ring, wherein the fusedbicyclic ring system also comprises an amino group at any position,except at the location of a heteroatom or at the location of a ringfusion. The heteroaromatic ring includes: pyridine, pyrimidine,pyrazine, pyridazine, triazine, imidazole, pyrazole, triazole, oxazole,and thiazole. Six-membered rings are preferred for both rings, andquinolines and isoquinolines are most preferred for the fused bicyclicring system.

A process is provided for synthesizing a racemic amino-substituted5,6,7,8-tetrahydroquinoline or a racemic amino-substituted5,6,7,8-tetrahydroisoquinoline comprising:

a) reacting an amino-substituted quinoline of the formula I or anamino-substituted isoquinoline of the formula II with anamine-protecting group compound in an organic solvent to produce anamine-protected, substituted quinoline or isoquinoline:

b) hydrogenating the amine-protected, substituted quinoline orisoquinoline in a strongly acidic solvent at an elevated temperature toform the 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;and

c) hydrolyzing the amine-protecting group to produce the desired racemicamino-substituted 5,6,7,8-tetrahydroquinoline or racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline;

wherein NH₂ is located at any position on the benzene portion of thequinoline or isoquinoline, R¹ is located at any other hydrogen positionon the quinoline or isoquinoline ring; m is 0-4; and wherein R¹ isselected from the group consisting of nitro, cyano, carboxylic acid,alkyl, alkoxy, cycloalkyl, a protected hydroxyl, a protected thiol, aprotected amino, acyl, carboxylate, carboxamide, sulfonamide, anaromatic group and a heterocyclic group.

For example, a preferred process for the synthesis of racemic8-amino-5,6,7,8-tetrahydroquinoline using selective hydrogenation isdescribed. (Scheme 1). The protocol involves starting with8-aminoquinoline 1, which is commercially available, and acetylating itto form the corresponding acetamide derivative 2:N-(quinoline-8-yl)-acetamide, using acetic anhydride in an organicsolvent. Subsequent hydrogenation of the acetamide in a strongly acidicsolvent at an elevated temperature forms the 5,6,7,8-tetrahydroquinoline3, and then the acetamide is cleaved via acid hydrolysis to produce thedesired racemic mixture or (R,S)-8-amino-5,6,7,8-tetrahydroquinolines 4.

An amino-substituted quinoline or isoquinoline is reacted with an amineprotecting group in an organic solvent to produce an amine-protectedquinoline or isoquinoline. The protecting group is utilized to preventhydrogenolysis of the desired amine during the hydrogenation. Therefore,any amine protecting group can be used, such as, an acyl, carbamate, orsulfonamide, and the like. The preferred amine protecting group is anacetyl. The amino substituted compound is reacted with acetic anhydrideto form the acetamide wherein the organic solvent is triethylamine(Et₃N) in dichloromethane with 4-dimethylaminopyridine (DMAP) as acatalyst.

The hydrogenation is carried out in a strongly acidic solvent, such astrifluoroacetic acid, hydrofluoric acid, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, trichloroacetic acid, acetic acid,or any combination thereof. The preferred solvent is trifluoroaceticacid.

Catalysts for the hydrogenation can include: platinum black, platinum oncarbon (0.5-20%), platinum on alumina (0.5-20%), platinum (IV) oxide,platinum (IV) oxide hydrate (Adam's catalyst), any other salts orcovalent compounds or coordination complexes of platinum that lead tothe generation of an active platinum (0) catalyst under the reactionconditions. The preferred catalysts include platinum (IV) oxide andAdam's catalyst. Catalyst loading is typically from 0.1% to 50% byweight, with the most preferred catalyst loading being 1 to 3% byweight.

The reaction temperatures for the hydrogenation reaction are typicallyelevated, with the temperature range from about 50 to about 150° C. withthe preferred temperature being from about 50 to about 70° C. and about60° C. being the most preferred. However, the hydrogenation reaction canbe conducted from about 20 to 50° C. if desired.

The reaction concentration is from about 0.01M to about 5M with thepreferred concentration from about 0.2M to about 0.5M; whereas, thehydrogen pressure is from about 0.1 to about 100 atmospheres, with thepreferred pressure at about 1 atmosphere. Reaction times are from about30 minutes to about 2 days and the preferred reaction time is from about2 to about 18 hours.

Preferably, the hydrogenation is performed with 0.3M of substrate in TFAusing 5 mol % of PtO₂ at 60° C. under 1 atmosphere of hydrogen. Alsopreferred is when the amino group is located at the 8-position of thequinoline, m is 0 or 1, and R¹ is methyl or methoxy.

Hydrolysis of the amide group to provide the corresponding amine isaccomplished by standard methods, including, but not limited to, heatingwith aqueous acid (for example, refluxing in 6N aqueous hydrochloricacid), heating with aqueous base (for example, refluxing in 6N aqueoussodium hydroxide), and heating in an appropriate solvent in the presenceof hydrazine.

Nitrosation Process

This invention also provides for the regioselective nitrosation of fusedbicyclic ring systems wherein the process involves the metallation ofthe saturated portion of the bicyclic ring with a strong base, followedby trapping the resultant anion with an appropriate nitrosating agent togive the corresponding nitrosyl compound. Spontaneous intramolecularrearrangement of this intermediate provides the oxime derivative. Theoxime may be reduced to form the corresponding amine derivative or maybe hydrolyzed to provide the corresponding ketone. The fused bicyclicring system comprises an optionally-substituted 5- or 6-memberedheteroaromatic ring fused to an optionally-substituted 5- or 6-memberedpartially or fully saturated cycloalkyl or heterocycloalkyl, such as,for example, a 5,6,7,8-tetrahydroquinoline or5,6,7,8-tetrahydroisoquinoline. The heteroaromatic ring includes:pyridine, pyrimidine, pyrazine, pyridazine, triazine, imidazole,pyrazole, triazole, oxazole and thiazole. The saturated ring includescyclohexane, piperidine, piperazine, hexahydropyridazine,tetrahydrofuran, tetrahydrothiophene, tetrahydropyran andtetrahydrothiapyran.

A process is described for synthesizing a racemic amino-substituted5,6,7,8-tetrahydroquinoline or a racemic amino-substituted5,6,7,8-tetrahydroisoquinoline comprising:

a) reacting either a substituted 5,6,7,8-tetrahydroquinoline of theformula III or a substituted 5,6,7,8-tetrahydroisoquinoline of theformula IV

with at least 2 equivalents of an alkyllithium base, or a lithium,sodium, or potassium amide base, and then with a nitrosating agent toform an oxime; and

b) reducing the oxime to produce the racemic amino-substituted5,6,7,8-tetrahydroquinoline or the racemic amino-substituted5,6,7,8-tetrahydroisoquinoline;

wherein the amino is located at the 8-position on the quinoline or the5-position on the isoquinoline; R² is located at any other hydrogenposition on the quinoline or isoquinoline ring; m is 0-4; and wherein R²is selected from the group consisting of halo, nitro, cyano, a protectedcarboxylic acid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, aprotected thiol, a protected amino, acyl, carboxylate, carboxamide,sulfonamide, an aromatic group and a heterocyclic group.

Further provided is a process for synthesizing a keto-substituted5,6,7,8-tetrahydroquinoline or a keto-substituted5,6,7,8-tetrahydroisoquinoline comprising:

a) reacting either a substituted 5,6,7,8 tetrahydroquinoline of theformula III or a substituted 5,6,7,8-tetrahydroisoquinoline of theformula IV

with at least 2 equivalents of an alkyllithium base, or a lithium,sodium, or potassium amide base; and then with a nitrosating agent toform an oxime; and

b) hydrolyzing the oxime to produce the corresponding ketone;

wherein the keto is located at the 8-position on the quinoline or the5-position on the isoquinoline; R² is located at any other hydrogenposition on the quinoline or isoquinoline; m is 0-4; and R² is selectedfrom the group consisting of halo, nitro, cyano, a protected carboxylicacid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, a protectedthiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide,an aromatic group, and a heterocyclic group.

This invention further provides a preferred alternative synthetic routefor (R,S)-8-amino-5,6,7,8-tetrahydroquinoline using nitrosation. (Scheme2). 5,6,7,8-Tetrahydroquinoline 5, which is commercially available, isutilized as the starting material and is reacted with a strong base inan organic ether to deprotonate the tetrahydroquinoline and then thetetrahydroquinoline is reacted with an alkyl nitrite to produce theoxime derivative 6: 6,7-dihydro-5H-quinolin-8-one oxime. Subsequentreduction of the oxime to the amine results in the racemic product 4:(R,S)-8-amino-5,6,7,8-tetrahydroquinoline. Alternatively, the oxime canbe hydrolyzed to produce 6,7-dihydro-5H-quinoline-8-one 7.

The nitrosation reaction is carried out in a solvent or combination ofsolvents, such as ethereal solvents (diethyl ether, diisopropyl ether,dibutyl ether, methyl tert-butyl ether, dipentyl ether, tert-amyl methylether, dimethoxy ether, 2-methoxyethyl ether, diethylene glycol dimethylether, diphenyl ether, dibenzyl ether, tetrahydrofuran, 1,4-dioxane, ormorpholine), aromatic solvents (benzene, toluene, ethylbenzene,o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene,o-dichlorobenzene, p-dichlorobenzene, 1,2,4-trichlorobenzene,naphthalene, pyridine, furan, or thiophene), dipolar aprotic solvents(carbon disulfide, dimethylformamide, dimethyl sulfoxide, or1-methyl-2-pyrrolidinone), alkane solvents (petroleum ether, mineralspirits, pentane, hexane, heptane, octane, isooctane, nonane, decane,hexadecane, 2-methylbutane, cyclopentane, or cyclohexane), and alkenesolvents (1-pentene, 1-hexene, cyclopentene, or cyclohexene). The mostpreferred solvents are the ethereal solvents, in particular, diethylether, methyl tert-butyl ether, tetrahydrofuran (THF), dimethoxyethane,2-methoxyethyl ether, and 1,4-dioxane. Preferred additives (activatingcosolvents) include tetramethylethylenediamine,pentamethyldiethylenetriamine, dimethylpropyleneurea, or hexamethylphosphoric triamide, or any combination thereof.

Reaction times for the metallation are from about 5 minutes to about 4hours, preferably from about 15 minutes to about 1 hour; whereas thereaction time for the nitrosation is from about 5 minutes to about 4hours, preferably from about 15 minutes to about 2 hours.

For the nitrosation, at least 2 equivalents of base are required,preferably from 2 to 3 equivalents, but less than 10 equivalents. Inaddition, the base must be sufficiently non-nucleophilic so as not toreact with the selected nitrosating agent. Therefore, bases utilized arealkyllithium bases (methyllithium, n-butyllithium, s-butyllithium,tert-butyllithium, isobutyllithium, phenyllithium, ethyllithium,n-hexyllithium, or isopropyllithium), lithium, sodium, or potassiumalkoxide bases (sodium methoxide, sodium ethoxide, or sodiumert-butoxide), or lithium, sodium, or potassium amide bases (lithiumamide, sodium amide, potassium amide, lithium hexamethyldisilazide,sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide, orlithium 2,2,6,6-tetramethylpiperidide) or any appropriate combinationthereof. Preferred bases are n-butyllithium, tert-butyllithium, lithiumdiisopropylamide, lithium dicyclohexylamide, lithium2,2,6,6-tetramethylpiperidide (LTMP), and potassiumhexamethyldisilazide, with LTMP as more preferred.

The temperature for the nitrosation reaction is from about −100° C. toabout 60° C., preferably between about −30° C. and about 0° C.

The concentration for the nitrosation reaction is from about 0.01M toabout 10M, preferably from about 0.2 to about 0.5M. Nitrosating agentsinclude: alkyl nitrites (n-butyl nitrite, s-butyl nitrite, tert-butylnitrite, isobutyl nitrite, isoamyl nitrite, n-amyl nitrite, ethylnitrite, isopropyl nitrite, or n-propyl nitrite) and alkyl dinitrites(1.3-propane dinitrite, 1,4-butane dinitrite, or 1,5-pentane dinitrite).Preferably the nitrosating agents are tert-butyl nitrite and isoamylnitrite. The equivalents of nitrosating agent utilized are from about0.5 to about 10 equivalents with about 2 to about 3 equivalentspreferred.

Preferably, nitrosation of 5,6,7,8-tetrahydroquinoline is carried out inTHF, at a temperature from about −40° C. to about −78° C., with aconcentration of about 0.2M and about 2.5 equivalents of LTMP. Alsopreferred are wherein the amino group is located at the 8-position ofthe 5,6,7,8-tetrahydroquinoline or at the 5 position of the5,6,7,8-tetrahydroisoquinoline; m is 0 or 1; and R² is methyl.

Reduction of the oxime is accomplished by standard methods, for example,hydrogen, methanol, and 10% palladium on carbon; hydrogen, methanol andRaney nickel; zinc metal in hydrochloric acid; or zinc metal intrifluoroacetic acid. In certain instances, it would be preferable toutilize a chiral hydrogenation catalyst or a chirally-modified reducingagent to enrich the production of the desired enantiomer.

Alternatively, the oxime can be hydrolyzed to provide the ketone viastandard methods, such as the use of aqueous 6N hydrochloric acid inacetone under reflux conditions or in aqueous 6N hydrochloric acid underreflux conditions.

Enzymatic Resolution Process

This invention provides for the use of enzymatic methods to resolveracemic mixtures of amino-substituted fused bicyclic ring systems,wherein the enzyme either selectively acylates or carbamoylates theracemic amine or mediates the hydrolysis, alcoholysis, or aminolysis ofracemic amides or carbamates. Each method provides a mixture of theamine enantiomer along with the opposite enantiomer of the amide orcarbamate. Separation of the enantiomers and subsequent cleavage of theamide or carbamate provides both enantiomers. The fused bicyclic ringsystem comprises an optionally-substituted 5- or 6-memberedheteroaromatic ring (ring C) an optionally-substituted 5- or 6-memberedpartially or fully saturated cycloalkyl or heterocycloalkyl (ring D).

The heteroaromatic ring includes: pyridine, pyrimidine, pyrazine,pyridazine, triazine, imidazole, pyrazole, triazole, oxazole andthiazole. The saturated ring includes cyclohexane, piperidine,piperazine, hexahydropyridazine, tetrahydrofuran, tetrahydrothiophene,tetrahydropyran and tetrahydrothiapyran.

This invention provides a process for resolving racemicamino-substituted 5,6,7,8-tetrahydroquinoline of the formula V orracemic amino-substituted 5,6,7,8-tetrahydroisoquinoline of the formulaVI to produce the two enantiomers:

comprising:

a) enantioselectively acylating or carbamoylating the racemicamino-substituted 5,6,7,8,-tetrahydroquinoline or the racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline using anenantioselective enzyme as a catalyst; and

b) separating the unreacted amino-substituted5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline as thefirst enantiomer, from the enantiomeric amide-or carbamate-substituted5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline; and

c) cleaving the amide or carbamate group to isolate the secondenantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or5,6,7,8-tetrahydroisoquinoline;

wherein NH₂ is located at any position on the saturated portion of thequinoline or isoquinoline; R² is located at any other hydrogen positionon the quinoline or isoquinoline ring; m is 0-4; and R² is selected fromthe group consisting of halo, nitro, cyano, carboxylic acid, alkyl,alkenyl, cycloalkyl, hydroxyl, thio, a protected amino, acyl,carboxylate, carboxamide, sulfonamide, an aromatic group and aheterocyclic group.

A preferred method also is described for using an enzyme to resolve theenantiomers of 8-amino-5,6,7,8-tetrahydroquinoline (Scheme 3). An enzymemay be used to catalyze the process in which a single enantiomer of aracemic mixture of 8-amino-5,6,7,8-tetrahydroquinoline reacts with asuitable ester, carboxylic acid or carbonate to give a mixture of eitherthe corresponding amide or carbamate, respectively, and the unreactedamine in enantiopure form (equations 1 and 2). This method may be usedto prepare either enantiomer of 8-amino-5,6,7,8-tetrahydroquinoline,either by isolation of the resolved amine or by cleavage of the amide orcarbamate group in the resolved, protected material.

For the esters, R7 is selected from the group consisting of H, loweralkyl (C1 through C12), alkenyl, alkynyl, aryl, heteroaryl, substitutedaryl, substituted heteroaryl, cycloalkyl, cycloalkenyl, carbocyclic,heterocyclic, benzyl, vinyl, and allyl; R8 is selected from the groupconsisting of H, lower alkyl (C1 through C12), vinyl, benzyl, allyl,trifluoroethyl, alkenyl, alkynyl, aryl, heteroaryl, substituted aryl,substituted heteroaryl, cycloalkyl, cycloalkenyl, carbocyclic, andheterocyclic. For the carbamates, R9 and R10 are the same or differentand are selected from the group consisting of lower alkyl (C1 throughC12), vinyl, allyl, benzyl, trifluoroethyl, alkenyl, alkynyl, aryl,heteroaryl, substituted aryl, substituted heteroaryl, cycloalkyl,cycloalkenyl, carbocyclic, and heterocyclic.

Another process is provided for resolving racemic amino-substituted5,6,7,8-tetrahydroquinoline or racemic amino-substituted5,6,7,8-tetrahydroisoquinoline to produce the two enantiomers,comprising:

a) reacting racemic amide-or carbamate-substituted5,6,7,8-tetrahydroquinoline of the formula VII or racemic amide-orcarbamate-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VIII

 with water, an alcohol, or a primary or secondary amine using anenantioselective enzyme as a catalyst to produce a mixture of thecorresponding amino in the first enantiomeric form, and the unreactedamide or carbamate in the second enantiomeric form;

b) separating the first enantiomer of the amino-substituted5,6,7,8-tetrahydroquinoline or amino-substituted5,6,7,8-tetrahydroisoquinoline, from the unreacted amide or carbamate;and

c) cleaving the amide or carbamate group to produce the secondenantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline oramino-substituted 5,6,7,8-isoquinoline;

wherein the amide or carbamate group is located at any position on thesaturated portion of the quinoline or isoquinoline; R² is located at anyother hydrogen position on the quinoline or isoquinoline ring; m is 0-4;R² is selected from the group consisting of halo, nitro, cyano,carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, aprotected amino, acyl, carboxylate, carboxamide, sulfonamide, anaromatic group and a heterocyclic group; and R³ is an optionallysubstituted carbon atom or an optionally substituted oxygen atom.

Alternatively, an enzyme may be used to catalyze the process in which aracemic mixture of a suitable amide or carbamate derived from8-amino-5,6,7,8-tetrahydroquinoline undergoes enantioselectivehydrolysis to give a single enantiomer of8-amino-5,6,7,8-tetrahydroquinoline and the parent amide or carbamate inenantiopure form (equations 3 and 4). This method may be used to prepareeither enantiomer of 8-amino-5,6,7,8-tetrahydroquinoline, either byisolation of the resolved hydrolyzed amine or by cleavage of the amideor carbamate group in the resolved, protected material.

Suitable enzymes for the above processes include (but are not limitedto) the following:

Lipases:

Candida antarctica (A and B)

Candida rugosa (also called Candida cylindracea)

Pseudomonas fluorescens (also called Pseudomonas cepacia; same asBurkholderia cepacia)

Pseudomonas aeruginosa

Alcaligenes sp. lipase

Burkholderia plantarii (Pseudomonas plantarii)

Pseudomonas sp. lipase

Chromobacterium viscosum lipase (Burkholderia glumae)

Porcine pancreatic lipase

Mucor sp. (Mucor miehei lipase)

Rhizopus delemar lipase

Rhizomucor miehei lipase

Rhizopus niveus and

Humicola lanuginosa;

Proteases:

Substilin Carlsberg and

Substilin BPN′; and

Penicillin acylase from Alcaligenes faecalis.

The use of certain enzymes to resolve selected racemic amines (or toselectively hydrolyze racemic amides) is described. See:

1. Reetz, M. T.; Driesbach, C. Chimia, 1994, 48, 570;

2. Iglesias, L. E.; Sanchez, V. M.; Rebolledo, F.; Gotor, V.Tetrahedron: Asymmetry, 1997, 8, 2675;

3. Takayama, S.; Lee, S. T.; Hung, S.-C.; Wong, C.-H. Chem. Commun.,1999, 2, 127;

4. Smidt, H.; Fisher, A.; Fisher, P.; Schmid, R. D. Biotechnol. Tech.,1996, 10, 335;

5. Koeller K. M., Wong C. H. Nature, 2001, 409, 232;

6. Carrea G., Riva S. Angew. Chem. Int. Ed. Engl. 2000, 39, 2226;

7. vanRantwijk F., Hacking M. A. P. J., Sheldon R. A. Monat. Chem. 2000,131, 549;

8. Hacking M. A. P. J., vanRantwijk F., Sheldon R. A. J. of MolecularCatalysis B:Enzymatic. 2000, 9, 201;

9. Gotor V. Biocat. Biotrans. 2000, 18, 87;

10. Morgan B., Zaks A., Dodds D. R., Liu J. C., Jain R., Megati S.,Njoroge F. G., Girijavallabhan V. M. J. Org. Chem. 2000, 65, 5451;

11. Kazlauskas, R. J.; Weissfloch, A. N. E.; J of Molecular CatalysisB:Enzymatic 1997, 3, 65-72;

12. Sanchez, V. M.; Rebolledo, F.; Gotor, V. Tet. Asym. 1997, 8, 37-40.

13. Wagegg, T.; Enzelberger, M. M.; Bomscheuer, U. T.; Schmid, R. D.Journal of Biotechnology, 1998, 61, 75-78;

14. Messina, F.; Botta, M.; Corelli, F.; Schneider, M. P.; Fazio, F. J.Org. Chem. 1999, 64, 3767-3769;

15. Soledad de Castro, M.; Dominguez, P.; Sinisterra, J. V. Tetrahedron2000, 56, 1387-1391;

16. Maestro, A.; Astrorga, C.; Gotor, V. Tet. Asym. 1997, 8, 3153-3159;

17. Balkenhohl, F.; Ditrich, K.; Hauer, B.; Ladner, W. J. Prakt. Chem.1997, 339, 381-384;

18. Luna, A.; Astorga, C.; Fulop, F.; Gotor, V. Tet. Asym. 1998, 9,4483-4487;

19. Van Langen, L. M.; Oosthoek, N. H. P.; Guranda, D. T.; Van Rantwijk,F.; Svedas, V. K.; Sheldon, R. A. Tet. Asym. 2000, 11, 4593-4600; and

20. Ami, E.; Horui, H. Biosci. Biotechnol. Biochem. 1999, 63, 2150-2156.

The enzymatic processes are preferably conducted utilizing a lipase orprotease as the enantioselective enzyme and are more preferably selectedfrom the group consisting of Candida antarctica A and B, Candida rugosa,Pseudomonas fluorescens, Substilin Carlsberg, Substilin BPN′, andAlcaligenes faecalis penicillin.

The acylating agent is either an optionally substituted acid, anoptionally substituted ester or an optionally substituted primary,secondary, or tertiary amide. The carbamoylating agent is an optionallysubstituted carbonate. Preferably, the acylating agent is ethyl acetateand the carbamoylating agent is dibenzyl carbonate or a dialkylcarbonate.

The enzymatic resolution is preferably carried out in a solvent orcombination of solvents such as: etheral solvents (e.g. diethyl ether,diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dipentylether, tert-amyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether,diethylene glycol dimethyl ether (diglyme), diphenyl ether, dibenzylether, tetrahydrofuran, 1,4-dioxane, morpholine, etc.), aromaticsolvents (e.g. benzene, toluene, ethylbenzene, o-xylene, m-xylene,p-xylene, xylenes, mesitylene, nitrobenzene, chlorobenzene,o-dichlorobenzene, p-dichlorobenzene, 1,2,4-trichlorobenzene,naphthalene, pyridine, 1-methylpyrrole, furan, thiophene, etc.),chlorinated alkyl solvents (e.g. methylene chloride, chloroform,dichloroethane, trichloroethylene, etc.), dipolar aprotic solvents (e.g.carbon disulfide, dimethylformamide, dimethyl sulfoxide,1-methyl-2-pyrrolidinone, acetonitrile, nitromethane, nitroethane,etc.), alkane solvents (e.g. petroleum ether, mineral spirits (ligroin),pentane, hexane, hexanes, heptane, octane, isooctane, nonane, decane,hexadecane, 2-methylbutane, cyclopentane, cyclohexane, etc.), alkenesolvents (e.g. 1-pentene, 1-hexene, cyclopentene, cyclohexene, etc.),ketone solvents (e.g. acetone, butanone, 2-pentanone, 3-pentanone,methyl isobutyl ketone, cyclopentanone, cyclohexanone, cycloheptanone,etc.), water. The enzymatic acylation or carbamoylation is preferablycarried out in either diisopropyl ether or methyl tert-butyl ether,although in these cases the acylating agent or the carbamoylating agentmay also be used as solvent. The preferred acylating agent in this caseis ethyl acetate, while the preferred carbamoylating agents are dibenzylcarbonate and diallyl carbonate. The preferred solvent for the enzymatichydrolysis, alcoholysis and aminolysis is water, although in these casesthe alcohol or amine nucleophile may also be used as solvent.

The reaction temperature is between about 0° C. to about 120° C. withthe preferred temperature from about 50 to about 60° C.

The concentration for the enzymatic resolution is from about 0.01M toabout 10M with respect to the starting substrate, with the preferredconcentration being from about 0.3 to about 0.6M, whereas the number ofequivalent enzyme to substrate is about 0.01 to about 10 by weight, withthe preferred equivalent being from about 0.3 to about 0.4 equivalentsby weight. Typically, the reaction time is from about 30 minutes toabout 48 hours, preferably from about 2 hours to about 6 hours.

The amide or carbamate substituted compounds are hydrolyzed usingstandard conditions, such as hydrochloric acid in acetone under refluxconditions or hydrochloric acid under reflux conditions. Preferably, theamino group is located at the 8-position of a5,6,7,8-tetrahydroquinoline or at the 5-position of a5,6,7,8-tetrahydroisoquinoline, m is 0 or 1, and R² is methyl.

Racemization Process

This invention provides a procedure to racemize the single enantiomersof optionally substituted amino-substituted fused bicyclic ring systemsXII, wherein treatment of the enantiomerically pure or enantiomericallyenriched amine, either as the primary, secondary or tertiary amine, oras an amine derivative, under the proscribed experimental conditionsconverts it to the racemate. In cases where the amine is substituted asan amine derivative (such as an amide, carbamate, or urea), hydrolysisof this functional group under acidic or basic conditions subsequent tothe racemization procedure affords the corresponding racemic amine. Thefused bicyclic ring system comprises an optionally-substituted 5- or6-membered heteroaromatic ring (ring C) fused to anoptionally-substituted 5- or 6-membered partially or fully saturatedcycloalkyl or heterocycloalkyl (ring D). The heteroaromatic ringincludes: pyridine, pyrimidine, pyrazine, pyridazine, triazine,imidazole, pyrazole, triazole, oxazole and thiazole. The saturated ringincludes cyclohexane, piperidine, piperazine, hexahydropyridazine,tetrahydrofuran, tetrahydrothiophene, tetrahydropyran andtetrahydrothiapyran. The optional substituents on the amino group (R⁷and R⁸ above) include: hydrogen, optionally substituted alkyl, aryl,heteroalkyl, heteroaryl, aralkyl, alkanoyl, alkylsulfonyl, a carbonyl orgroup substituted by an aromatic or heterocyclic ring, aryloxycarbonyl,alkoxycarbonyl, arylcarbamoyl, alkylcarbamoyl, arylthiocarbonyl,alkylthiocarbonyl, and carbamoyl.

This invention provides a process for racemizing a single enantiomer ofamino-substituted 5,6,7,8-tetrahydroquinoline of the formula XIII or ofamino-substituted 5,6,7,8-tetrahydroisoquinoline of the formula XIV toproduce the corresponding racemic mixture:

comprising:

a) heating an enantiomerically enriched amino-substituted5,6,7,8-tetrahydroquinoline or an enantiomerically enrichedamino-substituted 5,6,7,8-tetrahydroisoquinoline neat or in an organicsolvent in the presence or absence of an additive; and

b) when either R⁷ or R⁸ is not hydrogen, cleaving the R⁷ or R⁹ groupsunder conditions (e.g. acid-promoted hydrolysis in the case of amidesand carbamates) to afford the corresponding racemic amine,

wherein NR⁷R⁸ is located at any position on the saturated portion of thequinoline or isoquinoline; R² is located at any other hydrogen positionon the quinoline or isoquinoline ring; m is 0-4; and R is selected fromthe group consisting of halo, nitro, cyano, carboxylic acid, alkyl,alkenyl, cycloalkyl, hydroxyl, thio, a protected amino, acyl,carboxylate, carboxamide, sulfonamide, an aromatic group and aheterocyclic group.

A preferred method also is described for racemization of enantioenriched(R)- or (S)-8-amino-5,6,7,8-tetrahydroquinoline or enantioenriched (R)-or (S)-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-amides and carbamates(Scheme 4). This method may be used to racemize either enantiomer of8-amino-5,6,7,8-tetrahydroquinoline or its corresponding amides orcarbamates. In the case of the amides and carbamates, the amide andcarbamate groups may be cleaved to afford the corresponding amine. Ineither case, the racemic amine thus obtained may be resubmitted to theEnzymatic Resolution Process described above and thereby recycled.

For the amides, R⁹ is selected from the group consisting of H, C₁-C₁₂alkyl, alkenyl, alkynyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, cycloalkyl, cycloalkenyl, carbocyclic, heterocyclic, benzyl,vinyl, and allyl. For the carbamates, R¹⁰ is selected from the groupconsisting of C₁-C₁₂ alkyl, vinyl, allyl, benzyl, trifluoroethyl,alkenyl, alkynyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, cycloalkyl, cycloalkenyl, carbocyclic, and heterocyclic.

The racemization reaction is preferably carried out neat or in asolvent, or combination of solvents such as: etheral solvents (e.g.diethyl ether, diisopropyl ether, dibutyl ether, methyl tert-butylether, dipentyl ether, tert-amyl methyl ether, dimethoxy ethane,2-methoxyethyl ether, diethylene glycol dimethyl ether (diglyme),diphenyl ether, dibenzyl ether, tetrahydrofuran, 1,4-dioxane,morpholine, etc.), aromatic solvents (e.g. benzene, toluene,ethylbenzene, o-xylene, m-xylene, p-xylene, xylenes, mesitylene,nitrobenzene, chlorobenzene, o-dichlorobenzene, p-dichlorobenzene,1,2,4-trichlorobenzene, naphthalene, pyridine, 1-methylpyrrole, furan,thiophene, etc.), chlorinated alkyl solvents (e.g. methylene chloride,chloroform, dichloroethane, trichloroethylene, etc.), dipolar aproticsolvents (e.g. carbon disulfide, dimethylformamide, dimethyl sulfoxide,1-methyl-2-pyrrolidinone, acetonitrile, nitromethane, nitroethane,etc.), alkane solvents (e.g. petroleum ether, mineral spirits (ligroin),pentane, hexane, hexanes, heptane, octane, isooctane, nonane, decane,hexadecane, 2-methylbutane, cyclopentane, cyclohexane, etc.), alkenesolvents (e.g. 1-pentene, 1-hexene, cyclopentene, cyclohexene, etc.),ketone solvents (e.g. acetone, butanone, 2-pentanone, 3-pentanone,methyl isobutyl ketone, cyclopentanone, cyclohexanone, cycloheptanone,etc.), or water. The racemization of the unsubstituted primary amine orthe corresponding amide or carbamate is most preferably carried out neat(in the absence of solvent).

The reaction temperature is between about 0° C. to about 300° C. withthe preferred temperature from about 120° C. to about 150° C.

For the cases where a solvent is employed, the concentration for theracemization is from about 0.01M to about 10M with respect to thestarting substrate, with the preferred concentration being from about0.3 to about 0.6M.

The racemization reaction optionally may be carried out in the presenceof either a catalytic or stoichiometric amount of an appropriateadditive or combination of additives, such as a base, a Lewis acid, analdehyde or a ketone. Suitable bases include: lithium, sodium, potassiumor cesium hydroxide bases (KOH, NaOH, LiOH, CsOH), lithium, sodium,potassium or cesium alkoxide bases (sodium methoxide, sodium ethoxide,sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide,lithium methoxide), lithium, sodium, potassium hydride bases (LiH, NaH,KH), alkyllithium bases (methyllithium, n-butyllithium, s-butyllithium,tert-butyllithium, isobutyllithium, phenyllithium, ethyllithium,n-hexyllithium, or isopropyllithium), or lithium, sodium, or potassiumamide bases (lithium amide, sodium amide, potassium amide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, lithium diisopropylamide, lithium diethylamide,lithium dicyclohexylamide, or lithium 2,2,6,6-tetramethylpiperidide) orany appropriate combination thereof. Suitable Lewis acids include: metalsalts (AlCl₃, FeCl₃, CrCl₂, HgCl₂, CuCl, TiCl₄, Yb(OTf₃), InOTf,TiCl₂O′Pr₂, Ti(O′Pr)₄), organometallic species (trimethylaluminum,dimethylaluminum chloride), and boron species (BF₃, B(OMe₃), B(O′Pr)₃).Suitable aldehydes include: benzaldehyde, 4-methoxybenzaldehyde,2,6-dichlorobenzaldehyde, acetaldehyde, and formaldehyde. Suitableketones include: acetone, acetophenone, butanone, 2-pentanone andcyclohexanone. The preferred amount of the additive, in terms of thenumber of equivalents additive to substrate, is about 0.01 to about 10by weight, with the preferred equivalent being from about 0.1 to about 1equivalents by weight. The racemization of the unsubstituted primaryamine or the corresponding amide or carbamate is preferably carried outin the absence of an additive.

Typically, the reaction time is from about 30 minutes to about 48 hours,preferably from about 1 hour to about 2 hours.

The racemization is preferably carried out in the presence of an inertatmosphere, most preferably under an atmosphere of dry nitrogen orargon.

The racemic amide or carbamate substituted compounds are hydrolyzedusing standard conditions, such as hydrochloric acid in acetone underreflux conditions or hydrochloric acid under reflux conditions.Preferably, the amino group is located at the 8-position of a5,6,7,8-tetrahydroquinoline or at the 5-position of a5,6,7,8-tetrahydroisoquinoline, m is 0 or 1, R⁹ is methyl, and R¹⁰ ismethyl, allyl, or benzyl.

Asymmetric Synthesis Process

The invention also describes a process for the formation of astereodefined amino group by forming an imine between anenantiomerically pure primary amine chiral auxiliary group and a ketonesubstrate followed by diastereoselective reduction of the resultingimine to provide a secondary amine, and then removal of the chiralauxiliary to produce an enantiomer of the primary amino group on thesubstrate. Either enantiomeric form of the primary amine can beprepared. Alternatively, in a prestep, the ketone is formed by oxidizinga corresponding hydroxyl group under standard conditions.

A process is provided for synthesizing an enantiomer of a primaryamino-substituted fused bicyclic ring of formula IX comprising:

a) forming the Schiff base of a keto group located on ring B of thefused bicyclic ring by reacting it with an enantiomerically-pure primaryamine chiral auxiliary R*NH₂ of the formula X

 to produce the corresponding enantiomerically-pure imine of the fusedbicyclic ring;

b) diastercoselectively reducing the imine to produce the correspondingenantiomerically-pure secondary amine on the fused bicyclic ring; and

c) removing the chiral auxiliary R* to form the enantiomer of theprimary amino-substituted fused bicyclic ring;

wherein ring A is a heteroaromatic 5- or 6-membered ring, P is anitrogen atom, sulfur atom or oxygen atom; ring B is a 5- or 6-memberedpartially or fully saturated cycloalkyl or heterocycloalkyl;

wherein NH₂ is located at a position on ring B; and R² is located at anyother hydrogen position on the fused bicyclic ring;

wherein m is 0-4; R² is selected from the group consisting of halo,nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl,thiol, a protected amino, acyl, carboxylate, carboximide, sulfonamide,an aromatic group and a heterocyclic group; and R⁴, R⁵, and R⁶ are eachdifferent and selected from the group consisting of hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, and a 5- or 6-membered aromatic ring;and at least one of R⁴, R⁵, or R⁶ is a 5- or 6-membered aromatic orheteroaromatic ring.

A preferred process for the synthesis of enantiomerically enriched8-amino-5,6,7,8-tetrahydroquinoline using a chiral auxiliary isdescribed (Scheme 5). The protocol involves formation of the Schiff baseof 6,7-dihydro-5H-quinolin-8-one 10 with an appropriate enantiomericallypure primary benzylic amine (R*—NH₂) to give the imine 11. Subsequentreduction of 11 with a suitable hydride reagent (e.g. sodiumborohydride) followed by reductive cleavage of the chiral auxiliaryprovides the title compound 8 in enantiomerically pure (orenantiomerically enriched) form. This synthetic route may be adapted toprepare either enantiomer of 8 depending on the choice of chiralauxiliary.

Suitable chiral auxiliaries to be used in this sequence are of generalformula X, in which R⁴, R⁵, and R⁶ are non-equivalent. At least one ofR⁴—R⁶ must be an aromatic group (either a 5- or 6-membered aryl,heteroaryl, substituted aryl, or substituted heteroaryl); otherwise,R⁴—R⁶ may be composed from the list shown below:

Wherein R⁴, R⁵, and R⁶ are the same or different and are selected fromthe group consisting of H, alkyl (C₁ through C₁₂), alkenyl, alkynyl,aryl, heteroaryl, substituted aryl, substituted heteroaryl, cycloalkyl,cycloalkenyl, carbocyclic, heterocyclic, carboxylate, amide, carboxylicacid, and benzyl.

Examples of suitable chiral auxiliaries include (but are not limited to)the following:

(R) or (S)-1-phenylethylamine,

(R) or (S)-1-(1-naphthyl)ethylamine,

(R) or (S)-1-(2-naphthyl)ethylamine,

(R) or (S)-2-phenylglycinol,

(R) or (S)-1-(4-bromophenyl)ethylamine,

(R) or (S)-alpha-methyl-4-nitrobenzylamine,

(1S,2R) or (1R,2S)-2-amino-1,2-diphenylethanol,

(R) or (S)-1-phenylpropylamine,

(R) or (S)-1-(P-tolyl)ethylamine,

(1S,2R) or (1R,2S)-cis-1-amino-2-indanol,

(R) or (S)-1-aminoindan,

(R) or (S)-1-phenyl-2-(p-tolyl)ethylamine,

(R) or (S)-1-aminotetralin,

(R) or (S)-3-bromo-alpha-methylbenzylamine,

(R) or (S)-4-chloro-alpha-methylbenzylamine,

(R) or (S)-3-methoxy-alpha-methylbenzylamine,

(R) or (S)-2-methoxy-alpha-methylbenzylamine,

(R) or (S)-4-methoxy-alpha-methylbenzylamine,

(R) or (S)-3-amino-3-phenyl propan-1-ol, and

(R) or (S)-1-amino-1-phenyl-2-methoxyethane.

The chiral auxiliary compound is preferably phenylethylamine,naphthylethylamine, phenylpropylamine, or methoxyphenylethylamine, morepreferably (R)-(+)-phenylethylamine, (R)-(+)-1-phenylpropylamine, or(S)-(−)-1-(4-methoxyphenyl)ethylamine.

Suitable solvents for the formation of the imine and/or reduction of theimine to the amine include, alone or in combination,: ethereal solvents(diethyl ether, diisopropyl ether, dibutyl ether, methyl tert-butylether, dipentyl ether, tert-amyl methyl ether, dimethoxy ethane,2-methoxyethyl ether, diethylene glycol dimethyl ether, diphenyl ether,dibenzyl ether, tetrahydrofuran, 1,4-dioxane, or morpholine), aromaticsolvents (benzene, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene,mesitylene, nitrobenzene, chlorobenzene, o-dichlorobenzene,p-dichlorobenzene, 1,2,4-trichloroenzene, naphthalene, pyridine,1-methylpyrrole, furan, or thiophene), chlorinated alkyl solvents(methylene chloride, chloroform, dichloroethane, thrichloroethane),alkane solvents (petroleum ether, mineral spirits, pentane, hexane,heptane, octane, isooctane, nonane, decane, hexadecane, 2-methylbutane,cyclopentane, or cylohexane), and alcohol solvents (methanol, ethanol,propanol, isopropanol, n-butanol, isobutanol, s-butanol, pentanol,isoamyl alcohol, or cyclohexanol). Preferred solvents are chlorinatedalkyl solvents, such as methylene chloride, and alcohol solvents, suchas methanol and ethanol.

Reducing agents include: boron-based hydride reducing agents (sodiumborohydride, lithium borohydride, potassium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride, lithiumtri-sec-butylborohydride, lithium triethylborohydride, lithiumtrisiamylborohydride, catechol borane, 9-BBN, disiamyl borane, thexylborane, or borane), aluminum-based hydride reagents (diisobutylaluminumhydride, lithium aluminum hydride, or sodiumbis(2-methoxyethoxy)aluminum hydride), and hydrogen gas in combinationwith an appropriate metal catalyst (palladium on carbon, platinum oxide,Raney-nickel, rhodium on carbon, or ruthenium on carbon).

The number of equivalents of reducing agent is between about 0.2 andabout 10 equivalents, with preferably about 1 to about 2 equivalents.The concentration is about 0.01M to about 10M with respect to thestarting substrate, with preferably from about 0.2 to about 0.6M,whereas the temperature of the reaction is from about −100 to about 100°C., most preferably from about −30 to about 25° C.

The stoichometry between the starting bicyclic ring and the chiralauxiliary compound is about 1:0.5 to about 1:5, with 1:1 beingpreferred.

Removal of the chiral auxiliary is accomplished via standard methods,such as hydrogenation in an appropriate solvent or in the presence of ametal catalyst, or acid-mediated cleavage.

Preferably, the fused bicyclic ring is an amino-substituted5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline, m is 0 or1, and R² is methyl.

Also provided by this invention are novel intermediate compounds asshown in the examples. Most preferred are those that are enantiomeric.

The following examples are intended to illustrate, but not to limit, theinvention.

EXAMPLES Preparation of (R,S)-8-Amino-5,6,7,8-tetrahydroquinoline bySelective Hydrogenation of N-(Quinolin-8-yl)-acetamide

Preparation of N-(Quinolin-8-yl)-acetamide

To a stirred solution of 8-aminoquinoline (33.37 g, 0.231 mol), DMAP(4-dimethylaminopyridine) (1.40 g, 0.011 mol) and triethylamine (Et₃N)(37 mL, 0.265 mol) in CH₂Cl₂ (methylene chloride) (275 mL) was addedacetic anhydride (Ac₂O) (26.5 mL, 0.281 mol). After 20 hours thereaction mixture was poured into a saturated aqueous solution of NaHCO₃(sodium bicarbonate). The phases were separated and the aqueous phasewas extracted with ether (3×150 mL). The combined organic phases weredried (Na₂SO₄) (sodium sulfate), filtered and concentrated in vacuo toprovide 43.56 g (100%) of N-(quinolin-8-yl)-acetamide as a beige solid.This material was used without further purification in subsequent steps.¹H NMR (CDCl₃) δ 2.35 (s, 3H), 7.42-7.56 (m, 3H), 8.15 (dd, 1H, J=1.5,8.4 Hz), 8.76 (dd, 1H, J=1.8, 7.2 Hz), 8.79 (dd, 1H, J=1.5, 4.2 Hz),9.78 (br s, 1H); ¹³C NMR (CDCl₃) δ 25.5, 116.8, 121.8, 122.0, 127.8,128.3, 134.9, 136.8, 138.6, 148.5, 169.2. ES-MS m/z 187 (M+H).

Preparation of (R,S)-N-(5,6,7,8-Tetrahydroquinolin-8-yl)-acetamide

N-(Quinolin-8-yl)-acetamide (173.27 g, 0.930 mol) was dissolved intrifluoroacetic acid (TFA) (2.7 L) in a 10 L three-neck round bottomflask equipped with Teflon tubing for gas addition, temperature controlprobe and an overhead mechanical stirrer. The vigorously stirredsolution was warmed to 60° C. and degassed for 20 minutes with nitrogengas. Platinum oxide (PtO₂) (2.11 g, 9.3 mmol) was added as a solid.Hydrogen gas (H₂) was then slowly bubbled from the tank through thesolution. The reaction was complete after 5.5 h as determined by GC (gaschromatography) analysis of an aliquot of the reaction mixture. Thereaction mixture was then degassed with nitrogen and cooled to 30° C. Itwas filtered though a glass frit to remove the catalyst and the solventwas removed in vacuo. The resulting material was treated with saturatedaqueous NaOH (sodium hydroxide) solution until the solution reached pH14. The solution was extracted with CH₂Cl₂ (8×500 mL), dried magnesiumsulfate (MgSO₄), filtered and concentrated in vacuo. The crude materialwas purified by flash column chromatography on silica gel (elution with1% MeOH (methanol) in CH₂Cl₂, then 5% MeOH (methanol) in CH₂Cl₂) toprovide 95.37 g (54%) of(R,S)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-acetamide. ¹H NMR (CDCl₃): δ1.80-2.00 (m, 4H), 2.79-2.85 (m, 2H), 2.90-3.00 (m, 2H), 3.91 (s, 3H),7.95 (s, 1H), 8.93 (s, 1H); ¹³C NMR (CDCl₃) δ 22.8, 23.1, 28.9, 30.0,33.1, 52.5, 123.7, 132.5, 138.0, 148.2, 162.6, 166.5. ES-MS m/z 192(M+H).

Preparation of (R,S)-8-Amino-5,6,7,8-tetrahydroquinoline

8-Acetamido-5,6,7,8-tetrahydroquinoline (41.94 g, 0.220 mol) wasdissolved in 6 N HCl (hydrochloric acid) (550 mL) and was heated toreflux. After 17 hours the reaction mixture to room temperature and wastreated with saturated aqueous NaOH solution until it 14. The mixturewas then extracted with CH₂Cl₂ (4×500 mL), and the combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo. Theresulting crude material was purified by Kugelrohr distillation toprovide 29.62 g (91%) of (R,S)-8 amino-5,6,7,8-tetrahydroquinoline as acolorless oil. ¹H NMR (CDCl₃) δ 1.52-1.62 (m, 2H), 1.78-1.85 (m, 1H),1.91 (br s, 2H), 2.02-2.06 (m, 1H), 2.60-2.65 (m, 2H), 3.83-3.87 (m,2H), 6.91 (dd, 1H, J=8, 5 Hz), 7.21 (dd, 1H, J=8, 1 Hz), 8.26 (d, 1H,J=5 Hz); ¹³C NMR (CDCl₃) δ 19.6, 28.7, 31.7, 51.0, 121.3, 131.2, 136.4,146.7, 159.2. ES-MS m/z 149 (M+H).

Additional examples of the selective hydrogenation are provided in thetable in equation 6.

TABLE 1 Hydrogenation of substituted quinolines 1a-m (Equation 5)^(a)

Reaction Yield of Yield of Entry Compound R Time (h) 2 (%) 3 (%) 1 1a2-NHAc 18 69  0 2 1b 3-NHAc 3.5 63  1 3 1c 4-NHAc, 2-Me 20 78  0 4 1d5-NHAc 4.5 45 27 5 1e 6-NHAc 5 49 28 6 1f 7-NI-lAc 18 25 20 7 1g 8-NHAc2.5 52 15 8 1h 18-NHAc, 2-Me 3 57 15 9 1i 3-MeO 4 65   0c 10 1j 2-Ph 568 10 11 1k 2-COOMe 4 51 20 12 1l 3-COOMe 5 70 11 13 1m 6-COOMe 5 30 3914 1n 8-COOMe 2 36  28d ^(a)Unless otherwise noted, all reactions wereperformed with 0.3 M substrate in TFA using 5 mol% PtO₂ at 60° C. under1 atm hydrogen. The progress of each reaction was monitored by GC and/orTLC. Yields are for isolated, purified product. ^(b)Yields areapproximate as the reaction was performed on a small scale (30 mg 1f)with 20% PtO₂. ^(c)Trace amounts (˜2%) of hydrogenolyzed products weredetected (quinoline, 1, 2, 3, 4-THQ, 5, 6, 7, 8-THQ). ^(d)16% of thestarting material remained unreacted.

Preparation of 5,6,7,8-tetrahydroquinoline-3-carboxylic acid methylester

Representative procedure for small scale hydrogenation reactions. To a 2or 3-neck, 100 ml round bottom flask containing a stir bar was addedmethyl quinoline-3-carboxylate (170 mg, 0.908 mmol) and platinum(IV)oxide (10.3 mg, 5 mol %). The flask was equipped with two outlets sealedwith rubber septa and containing Teflon stopcocks. Trifluoroacetic acid(3.0 mL), which was purged with argon gas to remove oxygen, was addedvia a plastic syringe into the reaction flask under an atmosphere ofnitrogen. The stirred reaction mixture was flushed and the flask filledwith hydrogen gas via a needle from a balloon through one of thesepta-sealed outlets. The Teflon stopcocks were closed and the reactionmixture was warmed to 60° C. and stirred for 5 hours. The progress ofthe reaction was monitored by GC and TLC. The reaction mixture wascooled to room temperature and aqueous saturated sodium bicarbonatesolution was added until the mixture was neutral. The mixture was thenextracted with CH₂Cl₂ (3×30 mL), dried (MgSO₄), and the solvent wasremoved in vacuo. The crude material thus obtained was separated byflash chromatography (silica gel, 10% EtOAc in hexanes). The titlecompound was obtained as a yellowish liquid (121 mg, 70%) whichdisplayed: ¹H NMR (CDCl₃, 300 MHz): δ 1.80-2.00 (m, 4H), 2.79-2.85 (m,2H), 2.90-3.00 (m, 2H), 3.91 (s, 3H), 7.95 (s, 1H), 8.93 (s, 1H); ¹³CNMR (CDCl₃): δ 22.8, 23.1, 28.9, 30.0, 33.1, 52.5, 123.7, 132.5, 138.0,148.2, 162.6, 166.5; MS m/z: 192 (M+H⁺).1,2,3,4-Tetrahydroquinoline-3-carboxylic acid methyl ester also wasisolated (19 mg, 11%).

Using the representative procedure for small scale reactions:N-(quinol-2-yl)acetamide (164 mg, 0.881 mmol) providedN-(5,6,7,8-tetrahydroquinolin-2-yl)acetamide (114 mg, 69%);N-(quinol-3-yl)acetamide (138 mg, 0.741 mmol) providedN-(5,6,7,8-tetrahydroquinolin-3-yl)acetamide (89 mg, 63%);N-(quinol-5-yl)acetamide (158 mg, 0.849 mmol) providedN-(5,6,7,8-tetrahydroquinolin-5-yl)acetamide (72 mg, 45%) andN-(1,2,3,4-tetrahydroquinolin-5-yl)acetamide (44 mg, 27%);N-(quinol-6-yl)acetamide (143 mg, 0.768 mmol) providedN-(5,6,7,8-tetrahydroquinolin-6-yl)acetamide (71 mg, 49%) andN-(1,2,3,4-tetrahydroquinolin-6-yl)acetamide (40 mg, 28%),N-(quinol-8-yl)acetamide (186.1 mg, 0.999 mmol) providedN-(5,6,7,8-tetrahydroquinolin-8-yl)acetamide (118.3 mg, 62%)) andN-(1,2,3,4-tetrahydroquinolin-8-yl) acetamide (26.7 mg, 14%),2-phenylquinoline (162 mg, 0.781 mmol) provided2-phenyl-5,6,7,8-tetrahydroquinoline (111 mg, 68%) and2-phenyl-1,2,3,4-tetrahydroquinoline (20 mg, 10%). Reaction ofquinoline-2-carboxylic acid methyl ester (160 mg, 0.855 mmol) provided5,6,7,8-tetrahydroquinoline-2-carboxylic acid methyl ester (83 mg, 51%)and 1,2,3,4-tetrahydroquinoline-2-carboxylic acid methyl ester (33 mg,20%).

Preparation of N-(2-Methyl-5,6,7,8-tetrahydroquinolin-4-yl) acetamide

Reaction of N-(2-methyl-quinolin-4-yl)acetamide (136 mg, 0.679 mmol)using the general procedure for small scale hydrogenations (workup withNaOH in place of saturated NaHCO₃) providedN-(2-methyl-5,6,7,8-tetrahydroquinolin-4-yl) acetamide (109 mg, 78%): ¹HNMR δ 1.83-1.90 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.46-2.2.53 (m,2H), 2.84-2.87 (m, 2H), 7.18 (br s, 1H), 7.82 (br s, 1H); ¹³C NMR δ22.7,22.8,23.5,24.6,25.3, 33.1, 112.3,117.3, 143.7, 156.4, 157.3, 169.0;MS m/z: 205 (M+H⁺).

Preparation of N-(5,6,7,8-tetrahydroquinolin-7-yl) acetamide

Reaction of N-(quinol-7-yl)acetamide (33 mg, 0.177 mmol) using thegeneral procedure for small scale hydrogenations (workup with NaOH inplace of saturated NaHCO3) providedN-(5,6,7,8-tetrahydroquinolin-7-yl)acetamide (8.3 mg, 25%): 1H NMR □1.72-1.83 (m, 1H), 1.99 (s, 3H), 2.04-2.20 (m, 2H), 2.72-2.95 (m, 3H),3.25 (dd, 1H, J=5, 17 Hz), 4.29-4.40 (m, 1H), 5.72 (br s, 1H), 7.05 (dd,1H, J=4, 8 Hz), 7.38 (d, 1H, J=8 Hz), 8.35 (d, 1H, J=4 Hz); 13C NMR □23.9, 26.5, 28.7, 39.0, 45.6, 121.9, 131.4, 137.0, 147.7, 154.8, 170.1;MS m/z: 213 (M+Na+). N-(1,2,3,4-tetrahydroquinolin-7-yl)acetamide alsowas isolated (6.5 mg, 20%): 1H NMR □ 1.24-1.28 (s, 1H), 1.87-1.95 (m,2H), 2.70 (dd, 2H, J=6, 6 Hz), 3.28 (dd, 2H, J=5, 5 Hz), 6.46 (d, 1H,J=8 Hz), 6.84 (d, 1H, J=8 Hz), 6.93 (s, 1H), 7.03 (br s, 1H); 13C NMR □22.1, 24.7, 26.6, 37.9, 105.6, 108.3, 117.6, 129.6, 136.5, 145.1, 168.1;MS m/z: 213 (M+Na+).

Preparation of N-(2-Methyl-5,6,7,8-tetrahydroquinolin-8-yl) acetamide

Reaction of N-(2-methyl-quinol-8-yl)acetamide (159 mg, 0.795 mmol) usingthe general procedure for small scale hydrogenations (workup with NaOHin place of saturated NaHCO₃) providedN-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide (92 mg, 57%): ¹HNMR δ 1.57-1.66 (m, 1H), 1.77-1.86 (m, 2H), 2.02 (s, 3H), 2.44 (s, 3H),2.43-2.57 (m, 1H), 2.68-2.73 (m, 2H), 4.67-4.74 (m, 1H), 6.79 (br s,1H), 6.92 (d, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz); ¹³C NMR δ 21.6, 25.4,25.8, 29.6, 31.0, 53.0, 123.4, 131.4, 139.2, 155.9, 157.2, 172.2; MSm/z: 227 (M+Na⁺). N-(2-Methyl-1,2,3,4-tetrahydroquinolin-8-yl)acetamidealso was isolated (25 mg, 15%) as a tautomeric mixture of acyclic andcyclized isomers in an approximately 1:2 ratio which exhibited thefollowing data: ¹H NMR δ 1.21-1.25 (m), 1.45-1.61 (m), 1.90 (s),1.90-1.95 (m), 2.20 (s), 2.71-2.91 (m), 3.32-3.43 (m), 4.00 (br s), 6.56(dd, J=8, 8 Hz), 6.63 (dd, J=8, 8 Hz), 6.66 (br s), 6.83 (d, J=8 Hz),6.87 (d, J=8 Hz), 6.94 (d, J=8 Hz), 7.02 (d, J=8 Hz), 7.06 (br s); MSm/z: 205 (M+H⁺).

Preparation of 3-Methoxy-5,6,7,8-tetrahydroquinoline

Reaction of 3-methoxyquinoline (181 mg, 1.16 mmol) using the generalprocedure for small scale hydrogenations provided3-methoxy-5,6,7,8-tetrahydroquinoline(127 mg, 65%): ¹H NMR δ 1.74-1.93(m, 4H), 2.75 (dd, 2H, J=6, 6 Hz), 2.85 (dd, 2H, J=6, 6 Hz), 3.82 (s,3H), 6.88 (d, 1H, J=3 Hz), 8.06 (d, 1H, J=3 Hz); ¹³C NMR δ 23.0, 23.7,29.4, 32.0, 55.9, 121.5, 132.9, 134.9, 149.8, 154.1; MS m/z: 164.1(M+H⁺). A mixture (5 mg) of hydrogenolyzed products (quinoline,1,2,3,4-tetrahydroquinoline and 5,6,7,8-tetrahydroquinoline asdetermined by GC analysis by comparison with commercial samples) alsowas obtained.

Preparation of 5,6,7,8-tetrahydroquinoline-6-carboxylic acid methylester

Reaction of quinoline-6-carboxylic acid methyl ester (170 mg, 0.908mmol) using the general procedure for small scale hydrogenationsprovided 5,6,7,8-tetrahydroquinoline-6-carboxylic acid methyl ester (49mg, 30%): ¹H NMR δ 1.91-2.05 (m, 1H), 2.25-2.34 (m, 1H), 2.74-2.84 (m,1H), 2.90-3.11 (m, 4H), 3.74 (s, 3H), 7.06 (dd, 1H, J=4, 8 Hz), 7.39 (d,1H, J=8 Hz), 8.37 (d, 1H, J=4 Hz); ¹³C NMR δ 26.1, 31.2, 31.7, 39.6,52.3, 121.6, 130.5, 137.2, 147.6, 156.3, 175.7; MS m/z: 214 (M+Na⁺).1,2,3,4-Tetrahydroquinoline-6-carboxylic acid methyl ester also wasisolated (66 mg, 39%).

Preparation of 5,6,7,8-tetrahydroquinoline-8-carboxylic acid methylester

Reaction of quinoline-8-carboxylic acid methyl ester (156 mg, 0.833mmol) using the general procedure for small scale hydrogenationsprovided 5,6,7,8-tetrahydroquinoline-8-carboxylic acid methyl ester (58mg, 36%). 1,2,3,4-Tetrahydroquinoline-8-carboxylic acid methyl esteralso was isolated (45 mg, 28%): ¹H NMR δ 1.87-1.96 (m, 2H), 2.76-2.81(m, 2H), 3.40-3.45 (m, 2H), 3.83 (s, 3H), 6.43 (dd, 1H, J=7, 8 Hz), 7.03(d, 1H, J=7 Hz), 7.69 (d, 1H, J=8 Hz), 7.76 (br s, 1H); ¹³C NMR δ 21.2,28.2, 41.6, 51.7, 108.8, 113.9, 122.4, 129.8, 134.1, 148.8, 169.6; MSm/z: 192 (M+H⁺).

Preparation of N-(5,6,7,8-tetrahydroisoquinolin-1-yl)acetamide

Reaction of N-(isoquinol-1-yl)acetamide (159 mg, 0.854 mmol) using thegeneral procedure for small scale hydrogenations (workup with NaOH inplace of saturated NaHCO₃) providedN-(5,6,7,8-tetrahydroisoquinolin-1-yl)acetamide (96 mg, 59%): ¹H NMR δ1.74-1.76 (m, 4H), 2.16-2.19 (m, 3H), 2.60-2.70 (m, 2H), 2.70-2.76 (m,2H), 6.86 (d, 1H, J=5 Hz), 8.03 (d, 1H, J=5 Hz); ¹³C NMR δ 22.3, 22.8,23.8, 25.1, 29.6, 122.9, 144.4 (2C), 149.5, 150.2, 170.6; MS m/z: 213(M+Na⁺). N-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetamide also wasisolated (16 mg, 11%): ¹H NMR δ 2.28 (m, 3H), 2.96-3.01 (m, 2H),3.56-3.61 (m, 2H), 7.20 (d, 1H, J=8 Hz), 7.33-7.38 (m, 1H), 7.44-7.49(m, 1H), 8.27 (d, 1H, J=8 Hz); ¹³C NMR δ27.2, 28.7, 29.7, 39.3, 127.3,127.5, 128.0, 132.6, 137.9, 162.8, 188.0; MS m/z: 191 (M+H⁺).

Preparation of N-(5,6,7,8-tetrahydroisoquinolin-5-yl)acetamide

Reaction of N-(isoquinol-5-yl)acetamide (171 mg, 0.918 mmol) using thegeneral procedure for small scale hydrogenations (workup with NaOH inplace of saturated NaHCO₃) providedN-(5,6,7,8-tetrahydroisoquinolin-5-yl)acetamide (79 mg, 45%): ¹H NMR δ1.60-1.70 (m, 1H), 1.70-1.09 (m, 2H), 1.98 (s, 3H), 1.98-2.08 (m, 1H),2.65-2.68 (m, 2H), 5.03-5.11(m, 1H), 6.63 (br d, 1H), 7.08 (d, 1H, J=5Hz), 8.17 (s, 1H), 8.20 (d, 1H, J=5 Hz); ¹³C NMR δ 20.7, 23.7, 26.4,30.1, 47.1, 122.9, 133.3, 146.3, 147.5, 150.7, 170.1; MS m/z: 191(M+H⁺). N-(1,2,3,4-tetrahydroisoquinolin-5-yl)acetamide also wasisolated (35 mg, 20%).

Preparation of (R,S)-8-Amino-5,6,7,8-tetrahydroquinoline by Nitrosationof 5,6,7,8-Tetrahydroquinoline

Preparation of 6,7-Dihydro-5H-quinolin-8-one Oxime

A solution of 5,6,7,8-tetrahydroquinoline (10.83 g, 81.3 mmol) andlithium diisopropylamide (LDA) (22.80 mL, 163 mmol) in dry MTBE(tert-butyl methyl ether) (100 mL was stirred for 10 min while dry N₂(nitrogen) was purged through the system. The solution was then cooledin an acetone-dry ice bath to between −30° C. and −20° C. A 2.5 Msolution of ^(n)BuLi (n-butyllithium) in hexanes (101.0 mL, 253 mmol)was then added over a period of 5 min. The temperature of the coolingbath was maintained below −20° C. throughout the addition. The thusobtained orange/red mixture was then transferred via cannula to apre-cooled solution of isoamyl nitrite (38.40 mL, 285 mmol) in dry MTBE(100 mL) at −30° C.; the transfer took about 10 min. The resultingmixture was stirred at −30° C. for 40 min at which time water (4.80 mL)was added in one portion. The quenched mixture was slowly warmed toambient temperature. A brown solid precipitated from the crude mixtureand was collected via filtration. The solid isolate was redissolved inCH₂Cl₂ (300 mL) and then filtered to remove any insoluble material. Thesolvent was removed in vacuo and the residue was recrystallized from 1:1MTBE-hexanes to provide 10.05 g (75%) of the title compound as a beigesolid. ¹H NMR (CDCl₃) δ 1.87-1.96 (m, 2H), 2.81 (t, 2H, J=6 Hz), 2.93(t, 2H, J=8 Hz), 7.18 (dd, 1H, J=9, 6 Hz), 7.48 (dd, 1H, J=9, 1 Hz),8.52 (dd, 1H, J=6, 1 Hz), 9.63 (br s, 1H); ¹³C NMR (CDCl₃) δ 20.8, 23.8,28.9, 123.4, 134.5, 136.7, 148.2, 148.9, 152.7. ES-MS m/z 163 (M+H).

Preparation of 6,7-Dihydro-5H-quinolin-8-one

To a stirred solution of 6,7-dihydro-5H-quinolin-8-one oxime (220 mg,1.36 mmol) in acetone (5.0 mL) was added 6 N HCl (2.0 mL). The resultingmixture was heated to reflux for 16 h, then cooled to room temperature.The reaction mixture was rendered basic with a minimum amount of 3 NNaOH, then extracted with CH₂Cl₂ (3×30 mL), and the combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo. Flashchromatography of the crude material thus obtained (silica gel, 20:2:1CH₂Cl₂—MeOH—NH₄OH) afforded 161 mg (81%) of the title compound as a paleyellow solid. ¹H NMR (CDCl₃) δ 2.17-2.25 (m, 2H), 2.82 (t, 2H, J=7 Hz),3.04 (t, 2H, J=6 Hz), 7.37 (dd, 1H, J-=9, 6 Hz), 7.66 (dd, 1H, J=9, 1Hz), 8.71 (dd, 1H, J=6, 1 Hz); ¹³C NMR (CDCl₃) δ 22.2, 28.6, 39.2,126.6, 137.3, 140.5, 147.6, 148.6, 196.5. ES-MS m/z 148 (M+H).

Preparation of (R,S)-8-Amino-5,6,7,8-tetrahydroquinoline

A hydrogenation flask was charged with 6,7-dihydro-5H-quinolin-8-oneoxime (266 mg, 1.64 mmol) and MeOH (2.5 mL). The flask was flushed withnitrogen for 5 min, then 10% palladium on carbon (Pd/C) (26 mg) wasadded in a single portion. The resulting mixture was shaken in a Parrhydrogenator under 45 psi hydrogen for 18 h. The residual material wasfiltered through a cake of celite eluting with CH₂Cl₂ (20 mL), and thenthe solvent was removed in vacuo. This procedure afforded 243 mg (100%)of the title compound as a pale yellow oil. This material displayedspectra identical to those reported above.

Preparation of (R,S)-8-Amino-5,6,7,8-tetrahydroquinoline

To a mixture of 6,7-dihydro-5H-quinolin-8-one oxime (96 kg, 554 mol) inNH₄OH (243 kg), water (279 kg) and 50% NaOH (72 kg), was added aceticacid (40 kg). The line was rinsed with water (18 kg). The mixture wasadjusted to 50° C. (ca. 5° C./hr), then zinc dust (144 kg, 2216 mol) wasadded in 10 portions maintaining a maximum temperature of 65° C. Afterfinishing the addition, the reaction mixture was agitated for 10-16hours at 50° C., then in-process TLC as performed to confirm thecompletion of the reaction. The reaction mixture was adjusted to 22° C.,then NaCl (108 kg) and toluene (720 kg) were added. After agitating for1 hr, the mixture was filtered on a Celite pad and rinsed forward withtoluene (2 times 90 kg). The layers were separated and the organic layerwas set aside. To the aqueous layer, NaCl (45 kg) and toluene (720 kg)were added and the reaction mixture was filtered once more on a Celitepad. After layer separation, the organic layer was set aside. Theorganic layers were combined and concentrated under vacuum, thendissolved in dichloromethane. The resulting solution was washed with2.5% NaOH solution (45 kg) and NH₄OH (270 kg). The organic layer was setaside, and the aqueous layer was extracted with dichloromethane (297kg). After phase separation, the organic layers were combined andconcentrated to dryness to yield 69 kg (84% yield) of the titlecompound.

Enzymatic Resolution of (R,S)-8-Amino-5,6,7,8-tetrahydroquinoline

Preparation of (R)-(−)-N-(5,6,7,8-Tetrahydroquinolin-8-yl)-acetamide and(S)-(+)-8-amino-5,6,7,8-tetrahydroquinoline

A mixture of (R,S)-8-amino-5,6,7,8-tetrahydroquinoline (1.00 g, 6.75mmol), Candida antarctica lipase (Novozyme 435, 300 mg), and EtOAc(ethyl acetate) (2.64 mL, 27.0 mmol) in dry i-Pr₂O (diisopropyl ether)(15 mL) was heated to 60° C. and stirred vigorously for 3 h. At thistime, the reaction mixture was filtered through a sintered glass funneland concentrated. Flash chromatography of the crude material (silicagel, 10:1 CH₂Cl₂—MeOH then 20:2:1 CH₂Cl₂—MeOH—NH₄OH (ammoniumhydroxide)) afforded 0.62 g(R)-(−)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-acetamide (48%) in 97% ee(separated by chiral GC, J&W CycloSil B column, isothermal 150° C.,(S)-(+)-enantiomer_(rt)=84.25 min, (R)-(−)-enantiomer_(rt)=86.16 min).[α]_(D)=−177.5 (c 1.00, CHCl₃); ¹H NMR (CDCl₃) δ 1.57-1.63 (m, 1H),1.74-1.79 (m, 2H), 1.93 (s, 3H), 2.30-2.36 (m, 1H), 2.66-2.71 (m, 2H),4.78 (dd, 1H, J=14, 6 Hz), 6.97 (dd, 1H, J=8, 5 Hz), 7.13 (br s, 1H),7.29 (d, 1H, J=8 Hz), 8.19 (d, 1H, J=5 Hz); ¹³C NMR (CDCl₃) δ 19.5,23.1, 28.0, 29.3, 49.9, 50.6, 122.1, 132.9, 136.9, 146.4, 154.9, 170.3.ES-MS m/z 191 (M+H). Anal. Calcd. for C₁₁H₁₄N₂O.0.3H₂O: C, 67.53; H,7.52; N, 14.32. Found: C, 67.60; H, 7.20; N, 14.12.

Also isolated was 0.48 g (48%)(S)-(+)-8-amino-5,6,7,8-tetrahydroquinoline in >99% ee (separated bychiral GC, J&W CycloSil B column, initial temperature: 160° C., initialtime: 0 min, rate: 1° C./min, final temperature: 130° C., final time: 0min, (S)-(+)-enantiomer_(rt)=12.43 min, (R)-(−)-enantiomer_(rt)=13.13min). [α]_(D)=+124.1 (c 0.99, CHCl₃); ¹H NMR (CDCl₃) δ 1.52-1.62 (m,2H), 1.78-1.85 (m, 1H), 1.91 (br s, 2H), 2.02-2.06 (m, 1H), 2.60-2.65(m, 2H), 3.83-3.87 (m, 2H), 6.91 (dd, 1H, J=8, 5 Hz), 7.21 (dd, 1H, J=8,1 Hz), 8.26 (d, 1H, J=5 Hz); ¹³C NMR (CDCl₃) δ 19.6, 28.7, 31.7, 51.0,121.3, 131.2, 136.4, 146.7, 159.2. ES-MS m/z 149 (M+H).

Preparation of (R)-(−)-8-Amino-5,6,7,8-tetrahydroquinoline

A stirred solution of(R)-(−)-N-(5,6,7,8-tetrahydroquinolin-8-yl)-acetamide (230 mg, 1.21mmol, 97% ee) in 6 N aqueous HCl (4.0 mL) was heated to 130° C. for 2 h.At this time, the reaction mixture was cooled to room temperature andcautiously rendered basic with a minimum amount of saturated aqueousNaOH, then diluted with CH₂Cl₂ (10 mL). The phases were separated andthe aqueous phase was washed with CH₂Cl₂ (5×20 mL), then the combinedorganic phases were dried (MgSO₄) and concentrated. Flash chromatographythrough a plug of silica gel (elution with 20:2:1 CH₂Cl₂—MeOH—NH₄OH)afforded 143 mg (80%) of (R)-(−)-8-amino-5,6,7,8-tetrahydroquinoline in96% ee (separated by chiral GC, J&W CycloSil B column, initialtemperature: 160° C., initial time: 0 min, rate: 1° C./min, finaltemperature: 130° C., final time: 0 min, (S)-(+)-enantiomer_(rt)=12.43min, (R)-(−)-enantiomer_(rt)=13.13 min). [α]_(D)=−125.7 (c 0.56, CHCl₃);¹H NMR (CDCl₃) δ 1.52-1.62 (m, 2H), 1.78-1.85 (m, 1H), 1.91 (br s, 2H),2.02-2.06 (m, 1H), 2.60-2.65 (m, 2H), 3.83-3.87 (m, 2H), 6.91 (dd, 1H,J=8, 5 Hz), 7.21 (dd, 1H, J=8, 1 Hz), 8.26 (d, 1H, J=5 Hz); ¹³C NMR(CDCl₃) δ 19.6, 28.7, 31.7, 51.0, 121.3, 131.2, 136.4, 146.7, 159.2.ES-MS m/z 149 (M+H).

Further examples of enzymatic resolution are provided in the tablebelow.

TABLE 2 Enzymatic resolution of amines using Candida antarctica lipase

conversion^(b) ee^(c) (%) isolated yield (%) substrate conditions^(a)(%) (S)-1 (R)-2 (S)-1 (R)-2

A 50 >99 98 48 48

A 50 >99 98 48 48

A 51 99 94 43 51

B 50 99 98 45 47

B 50 99 98 43 47

A 51 91 88 38 48

B 55 99 79 42 55

A 58 61 45 41 55

A 55 94 79 39 53

A 56 43 46 N/d N/d ^(a)All reactions were performed at 60° C. Reactiontimes varied from 2 h to 24 h. Condition A: reaction carried out inisopropyl ether with 4-5 equiv EtOAc; Condition B: reaction carried outin neat EtOAc. ^(b)Percent conversion determined by ¹H NMR. .^(c)Enantiomeric excess determined by chiral GC.

General Procedure for Resolution Reaction

A mixture of the amine (1 equiv; ˜0.2 M), Candida antarctica lipase B(Novozyme 435) (30 wt %) and ethyl acetate (4-5 equiv) in dry isopropylether (Condition A) or neat ethyl acetate (Condition B) were heated to60° C. and stirred vigorously. Anhydrous solvents (99.9%) purchased fromAldrich were used. The progress of the reaction was monitored by GCusing a chiral J&W CycloSil B column. Upon completion of the reaction(typically 2-24 hours) the mixture was filtered through a glass sinteredfunnel, was washed with EtOAc or methanol and concentrated in vacuo. Theunreacted amine and the acetamide were separated by chromatography onsilica gel. The enantiomeric excess of the amine and the acetamide weredetermined by chiral GC by comparison of the retention times withindependently prepared racemic samples. Optical rotations were measuredusing a P3001 Kruss polarimeter.

Preparation of (R)-N-(5,6,7,8-tetrahydroquinolin-5-yl)acetamide and(S)-5,6,7,8-tetrahydroquinolin-5-ylamine

Following the general procedure, 5,6,7,8-tetrahydroquinolin-5-ylamine(213.2 mg, 1.44 mmol), CALB (64 mg), EtOAc (0.56 mL) and iPr₂O (4.8 mL)were stirred for 6 hours. The conversion determined from ¹H NMR byintegration of the peaks at 5.07 ppm (CHNHAc) and 3.91 ppm (CHNH₂) was50%. Flash chromatography of the material on silica gel using 1:10MeOH:CH₂Cl₂ then 20:2:1 CH₂Cl₂—MeOH—NH₄OH furnished(R)-N-(5,6,7,8-tetrahydroquinolin-5-yl)acetamide ((132 mg, 48%) in 98%ee (chiral GC method: isothermal at 85° C. for 220 minutes ramp 5°C./min to 210° C., hold 5 min, (S)-enantiomer_(rt)=248.2 min,(R)-enantiomer_(rt)=248.5 min); [α]_(D)=+110° (c 1.32, CHCl₃); ¹H NMR(CDCl₃, 300 MHz) δ 1.69-1.81 (m, 1H), 1.84-2.00 (m, 2H), 2.04 (s, 3H),2.01-2.18 (m, 1H), 2.86-2.99 (m, 2H), 5.19-5.27 (m, 1H), 5.78 (br s,11H), 7.10 (dd, 1H, J=7.8, 4.8 Hz), 7.58 (d, 1H, J=7.8 Hz), 8.41 (d, 1H,J=4.8 Hz); ¹³C NMR (CDCl₃) δ 20.2, 23.8, 30.1, 32.6, 47.4, 121.9, 133.0,136.9, 148.7, 157.7, 170.0; MS m/z: 191 (M+H⁺). The unreacted(S)-5,6,7,8-tetrahydroquinolin-5-ylamine (was isolated in 48% yield (103mg) and 99% ee (chiral GC: (S)-enantiomer_(rt)=236.0 min,(R)-enantiomer_(rt)=236.6 min); [α]_(D)=+39° (c 1.03, CHCl₃); ¹H NMR(CDCl₃, 300 MHz) δ 1.50-1.70 (m, 3H), 1.74-1.85 (m 1H), 1.86-2.09 (m,2H), 2.76-2.99 (m, 2H), 3.94 (m, 1H), 7.07 (dd, 1H, J=7.8, 4.5 Hz), 7.70(d, 1H, J=7.8 Hz), 8.35 (dd, 1H, J=4.5, 1.5 Hz); ¹³C NMR (CDCl₃) δ 19.8,32.9, 34.0, 49.6, 121.7, 136.2, 136.6, 148.1, 157.3; MS m/z: 149 (M+H⁺).

Preparation of (R)-N-(5,6,7,8-tetrahydroisoquinolin-5-yl)acetamide and(S)-5,6,7,8-tetrahydroisoquinolin-5-ylamine

Following the general procedure, 5,6,7,8-tetrahydroisoquinolin-5-ylamine(268.3 mg, 1.81 mmol), CALB (80 mg), EtOAc (0.71 mL) and iPr₂O (6.0 mL)were stirred for 23 hours. The conversion determined from ¹H NMR byintegration of the peaks at 5.16 ppm (CHNHAc) and 3.90 ppm (CHNH₂) was51%. Flash chromatography of the material on silica gel using 1:4MeOH:CH₂Cl₂ then 4:1:1 CH₂Cl₂—MeOH—NH₄OH furnished the(R)-N-(5,6,7,8-tetrahydroquinolin-5-yl)acetamide ((181 mg, 51%) in 94%ee (chiral GC method: 160° C. for 20 min, ramp rate 5° C./min to 200°C., hold at 200° C. for 20 min, (S)-enantiomer_(rt)=38.3min,(R)-enantiomer_(rt)=39.1 min); [α]_(D)=+95° (c 1.81, CHCl₃); ¹H NMR(CDCl₃, 300 MHz) δ 1.58-1.69 (m, 1H), 1.70-1.92 (m, 2H), 1.96 (s, 3H),1.94 (2.04 (m, 1H), 2.61-2.68 (m, 2H), 5.00-5.10 (m, 1H), 6.82 (br d,1H, J=8.7 Hz), 7.05 (d, 1H, J=5.4 Hz), 8.13 (s, 1H), 8.17 (d, 1H, J=5.4Hz); ¹³C NMR (CDCl₃) δ 18.6, 21.6, 24.4, 28.1, 45.1, 120.9, 131.4,144.6, 145.4, 148.6, 168.4; MS m/z: 191 (M+H⁺), 132 (M−NHAc). Theunreacted (S)-5,6,7,8-tetrahydroisoquinolin-5-ylamine (was isolated in43% yield (114 mg) and 99% ee (chiral GC: (S)-enantiomer_(rt)=15.9 min,(R)-enantiomer_(rt)=16.2 min); [α]_(D)=+63° (c 1.14, CHCl₃). ¹H NMR(CDCl₃, 300 MHz) δ 1.26-1.69 (m, 3H), 1.70-1.85 (m, 1H), 1.86-2.11 (m,2H), 2.67-2.79 (m, 2H), 3.91 (t, 1H, J=5.4 Hz), 7.32 (d, 1H, J=4.3 Hz),8.32 (s, 1H), 8.37 (d, 1H, J=4.3 Hz); ¹³C NMR (CDCl₃) δ 20.1, 26.7,33.7, 49.3, 122.5, 132.6, 147.6, 149.9, 150.8; MS m/z: 149 (M+H⁺), 132(M−NH₂).

Preparation of (R)-N-(5,6,7,8-tetrahydroquinoxalin-5-yl)acetamide and(S)-5,6,7,8-tetrahydroquinoxalin-5-ylamine

Following the general procedure, 5,6,7,8-tetrahydroquinoxalin-5-ylamine(263 mg, 1.76 mmol), CALB (45 mg) and EtOAc (7.0 mL) were stirred for 2hours. The conversion determined from ¹H NMR by integration of the peaksat 4.94 ppm (CHNHAc) and 4.01 ppm (CHNH₂) was 50%. Flash chromatographyof the material on silica gel using 1:4 MeOH:EtOAc followed by 1:1:4NH₄OH:MeOH:EtOAc furnished the(R)-N-(5,6,7,8-tetrahydroquinoxalin-5-yl)acetamide ((157 mg, 47%) in 98%ee (chiral GC method: 130° C. for 180 min, (S)-enantiomer_(rt)=183.5min, (R)-enantiomer_(rt)=183.7 min); [α]_(D)=−78° (c 1.40, CHCl₃); ¹HNMR (CDCl₃, 300 MHz) δ 1.62-1.75 (m, 1H), 1.85-2.04 (m, 2H), 2.06 (s,3H), 2.48-2.57 (m, 1H), 2.90-3.13 (m, 2H), 4.96-5.03 (m, 1H), 6.34 (brs, 1H), 8.35 (d, 1H, J=2.4 Hz), 8.39 (d, 1H, J=2.4 Hz); ¹³C NMR (CDCl₃)δ 19.9, 23.6, 29.7, 31.8, 50.6, 142.1, 143.3, 152.0, 154.0, 170.7; MSm/z: 214 (M+Na⁺). The unreacted(S)-5,6,7,8-tetrahydroquinoxalin-5-ylamine (was isolated in 45% yield(118 mg) and 99% ee ((S)-enantiomer_(rt)=25.9 min,(R)-enantiomer_(rt)=29.0 min); [α]_(D)=+61° (c 0.71, CHCl₃); ¹H NMR(CDCl₃, 300 MHz): δ 1.62-1.79 (m, 1H), 1.80-2.18 (m, 4H), 2.18-2.30 (m,1H), 2.91-3.01 (m, 2H), 4.07 (dd, 1H, J=8.4, 5.4 Hz), 8.32-8.38 (m, 2H);¹³C NMR (CDCl₃): δ 19.7, 31.7, 32.2, 51.5, 142.0, 142.5, 152.6, 155.4;MS m/z: 150 (M+H⁺), 133 (M-NH₂).

Preparation of (R)-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamideand (S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine

Following the general procedure,3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (243 mg, 1.62 mmol), CALB(73 mg) and EtOAc (6.0 mL) were stirred for 2 hours. The conversiondetermined from ¹H NMR by integration of the peaks at 7.93 ppm and 8.16ppm was 50% (CHNH₂ and CHNHAc signals were not distinct). Flashchromatography of the material on silica gel using 1:10 MeOH:CH₂Cl₂followed by 1:1:10 NH₄OH:MeOH:CH₂Cl₂ furnished the(R)-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide ((145 mg, 47%)in 98% ee (chiral GC method: 140° C. for 16 min, ramp rate 5° C./min to160° C., hold at 160° C. for 50 min, (S)-enantiomor_(rt)=41.5 min,(R)-enantiomer_(rt)=40.9 min); [α]_(D)=−69° (c 1.45, CHCl₃); ¹H NMR(CDCl₃, 300 MHz) δ 1.91-2.00 (m, 1H), 1.97 (s, 3H), 2.47-2.57 (m, 1H),4.18-4.22 (m, 2H), 4.85-4.92 (m, 1H), 6.97 (m, 2H), 7.24 (br s, 1H),7.93-7.95 (dd, 1H, J=1.8, 3.9 Hz); ¹³C NMR (CDCl₃) δ 23.3, 28.9,47.2,64.4, 124.3, 124.7, 141.3, 141.7, 152.0, 170.9; MS m/z: 215 (M+Na⁺). Theunreacted (S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine (wasisolated in 43% yield (104 mg) and 99% ee ((S)-enantiomer_(rt)=14.7 min,(R)-enantiomer_(rt)=15.6 min); [α]_(D)=−13° (c 0.72, CHCl₃); ¹H NMR(CDCl₃, 300 MHz): δ 1.84 (br s, 2H), 1.90-2.01 (m, 1H), 2.24-2.34 (m,1H), 4.12 (dd, 1H, J=5.7, 6.9 Hz), 4.18-4.26 (m, 1H), 4.28-4.36 (m, 1H),7.06-7.13 (m, 2H), 8.15 (dd, 1H, J=1.8, 3.6 Hz); ¹³C NMR (CDCl₃) δ 31.5,47.8, 64.2, 123.8, 124.5, 142.1, 147.0, 151.1; MS m/z: 151.0 (M+H⁺),134.0 (M−NH₂); Anal. Calc. for C₈H₁₀N₂O.0.1H₂O: C; 63.22; H, 6.76; N,18.43. Found: C, 62.99; H, 6.81; N, 18.22.

Preparation of (R)-N-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamideand (S)-2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine

Following the general procedure,2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine (412.7 mg, 2.78 mmol),CALB (128 mg), EtOAc (0.63 mL) and iPr₂O (7 mL) were stirred for 9hours. The conversion determined from ¹H NMR by integration of the peaksat 4.73 ppm (CHNHAc) and 4.00 ppm (CHNH₂) was 51%. Flash chromatographyof the material on silica gel using 1:10 MeOH:CH₂Cl₂ then 10:1:1CH₂Cl₂—MeOH—NH₄OH furnished(R)-N-(2-methyl-5,6,7,8-tetrahydroquinolin-8-yl)acetamide ((167 mg, 47%)in 88% ee (chiral GC method: initial temperature 140° C., initial time22 minutes, ramp rate 1° C./min, final temperature 150° C., final time70 min, (S)-enantiomer_(rt)=89.4 min, (R)-enantiomer =91.6 min);[α]_(D)=−102° (c 1.67, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ 1.56-1.66 (m,1H), 1.82-1.91 (m, 2H), 2.08 (s, 3H), 2.51 (s, 3H), 2.61 (ddd, 1H,J=13.2, 5.1, 5.1 Hz), 2.76 (t, 1H, J=6.6 Hz), 4.72-4.79 (m, 1H), 6.61(br s, 1H), 6,98 (d, 1H, J=7.8 Hz), 7.31 (d, 1H, J=7.8 Hz); ¹³C NMR(CDCl₃) δ 20.1, 23.8, 24.2, 28.2, 29.6, 51.5, 122.4, 130.1, 137.8,154.4, 155.7, 170.8; MS m/z: 205 (M+H⁺), 146 (M-NHAc). The unreacted(S)-2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine (was isolated in 38%yield (107 mg) and 91% ee (chiral GC: (S)-enantiomer_(rt)=19.9 min,(R)-enantiomer_(rt)=20.6 min); [α]_(D)=+65° (c 1.07, CHCl₃); ¹H NMR(CDCl₃, 300 MHz) δ 1.62-1.82 (m, 2H), 1.84-2.00 (m, 3H), 2.11-2.20 (m,1H), 2.49 (s, 3H), 2.61-2.82 (m, 2H), 3.93-4.00 (m, 1H), 6.91 (d, 1H,J=7.8 Hz), 7.25 (d, 1H, J=7.8 Hz); ¹³C NMR (CDCl₃) δ 20.4, 24.6, 29.1,32.6, 51.8, 121.7, 128.6, 137.6, 155.9, 159.0; MS m/z: 163 (M+H⁺).

Preparation of (R)-N-(6,7-dihydro-5H-[1]pyrindin-7-yl)acetamide and(S)-6,7-dihydro-5H-[1]pyrindin-7-ylamine

Following the general procedure,6,7-dihydro-5H-[1]pyrindin-7-ylamine(271 mg, 2.02 mmol), CALB (81 mg)and EtOAc (6.5 mL) were stirred for 7 hours. The conversion determinedfrom ¹H NMR by integration of the peaks at 5.17 ppm (CHNHAc) and 4.21ppm (CHNH₂) was 55%. Flash chromatography of the material on silica gelusing 1:10 MeOH:CH₂Cl₂ followed by 1:1:4 NH₄OH:MeOH:CH₂Cl₂ furnished(R)-N-(6,7-dihydro-5H-[1]pyrindin-7-yl)acetamide ((194 mg, 41%). The twoenantiomers of the acetamide could not be resolved by GC nor HPLC, andhence the % ee had to be determined indirectly. A small sample of theacetamide was treated with 1N HCl to convert it to the amine, and theresulting amine was resolved by chiral GC (chiral GC method: 85° C. for120 min, ramp rate 5° C./min to 210° C., final time 5 min;(S)-enantiomer_(rt)=124.3 min, (R)-enantiomer_(rt)=126.1 min) to give %ee of 79%; [α]_(D)=−41° (c 1.49, CHCl₃); ¹H NMR (CDCl₃, 300 MHz) δ1.75-1.89 (m, 1H), 2.07 (s, 3H), 2.80-2.98 (m, 3H), 5.19-5.27 (m, 1H),6.32 (br s, 1H), 7.14 (dd, 1H, J=7.5, 5.0 Hz), 7.55 (d, 1H, J=7.5 Hz),8.39 (d, 1H, J=4.5 Hz); ¹³C NMR (CDCl₃) δ 23.6, 28.3, 33.9, 55.7, 123.0,133.3, 137.2, 148.2, 148.4, 162.7, 171.0. The unreacted(S)-6,7-dihydro-5H-[1]pyrindin-7-ylamine (was isolated in 42% yield (113mg) and 99% ee (chiral GC, (S)-enantiomer_(rt)=124.3 min,(R)-enantiomer_(rt)=126.1 min) and displayed spectra identical to thestarting material: ¹H NMR (CDCl₃, 300 MHz) δ 1.68-1.88 (m, 1H),2.50-2.61 (m, 3H), 2.75-2.86 (m, 1H), 2.92 (ddd, 1H, J=13.2, 9.0, 3.0Hz), 4.32 (dd, 1H, J=7.8, 7.8 Hz), 7.08 (dd, 1H, J=7.8, 4.8 Hz), 7.51(d, 1H, J=7.8 Hz), 8.40 (d, 1H, J=4.8 Hz). The dark color of the amineafter purification by column chromatography prevented determination ofits optical rotation.

Preparation of(R)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetamide and(S)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine

Following the general procedure,6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine (195 mg, 1.20mmol), CALB (59 mg), EtOAc (0.48 mL) and iPr₂O (4.6 mL) were stirred for24 hours. The conversion determined from ¹H NMR by integration of thepeaks at 5.05 ppm (CHNHAc) and 4.34 ppm (CHNH₂) was 58%. Flashchromatography of the material on silica gel using 1:10 MeOH:CH₂Cl₂followed by 1:1:4 NH₄OH:MeOH:CH₂Cl₂ furnished the(R)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetamide ((134mg, 55%) in 45% ee (chiral GC method: 180° C. for 15 min, ramp rate of10° C./min to 210° C., hold 10 min, (S)-(−)-enantiomer_(rt)=17.4 min,(R)-(+)-enantiomer_(rt)=17.1 min); [α]_(D)=−10° (c 1.34, CHCl₃); ¹H NMR(CDCl₃, 300 MHz) 61.09-1.31 (m, 2H), 1.80-2.03 (m, 3H), 2.06 (s, 3H),2.24 (d, 1H, J=13.5 Hz), 2.65-2.71 (m, 1H), 2.75-2.85 (m, 1H), 4.96-5.01(m, 1H), 7.06 (dd, 1H, J=7.0, 4.8 Hz), 7.38 (d, 1H, J=7.0 Hz), 8.11 (brs, 1H), 8.28 (d, 1H, J=4.8 Hz); ¹³C NMR (CDCl₃) δ 24.0, 27.3, 30.1,34.5, 34.8, 53.8, 122.8, 137.0, 137.5, 145.5, 159.2, 169.6; MS m/z: 205(M+H⁺). The unreacted(S)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine (was isolatedin 41% yield (81 mg) and 61% ee (chiral GC, (S)-enantiomer_(rt)=5.81min, (R)-enantiomer_(rt)=6.00 min); [α]_(D)=+2° (c 1.13, CHCl₃); anddisplayed spectra identical to the starting material: ¹H NMR (CDCl₃, 300MHz) δ 1.20-1.35 (m, 1H), 1.36-1.53 (m, 1H), 1.75-2.01 (m, 4H), 2.15 (brs, 2H), 2.69-2.77 (m, 2H), 4.16 (d, 1H, J=8.7 Hz), 6.95-7.06 (m, 1H),7.32 (d, 1H, J=6.0 Hz), 8.34 (br s, 1H).

Preparation of (R)-N-(4,5,6,7-tetrahydrobenzofuran-7-yl)acetamide and(S)-4,5,6,7-tetrahydrobenzofuran-7-ylamine

Following the general procedure, 4,5,6,7-tetrahydrobenzofuran-7-ylamine(150 mg, 1.09 mmol), CALB (45 mg), EtOAc (0.43 mL) and iPr₂O (4.0 mL)were stirred for 17 hours. The conversion determined from ¹H NMR byintegration of the peaks at 5.09 ppm (CHNHAc) and 3.95 ppm (CHNH₂) was55%. Flash chromatography of the material on silica gel using 1:20MeOH:CH₂Cl₂ followed by 1:1:4 NH₄OH:MeOH:CH₂Cl₂ furnished(R)-N-(4,5,6,7-tetrahydrobenzofuran-7-yl)acetamide ((104 mg, 53%) in 79%ee (chiral GC method: 120° C. for 15 min, ramp rate of 2° C./min to 160°C., hold 20 min at 160° C., (S)-(−)-enantiomer_(rt)=43.6 min,(R)-(+)-enantiomer_(rt)=45.8 min); [α]_(D)=+58° (c 1.04, CHCl₃); ¹H NMR(CDCl₃, 300 MHz) δ 1.65-1.86 (m, 3H), 1.90-1.2.04 (m, 1H), 1.94 (s, 3H),2.30-2.50 (m, 2H), 5.09 br s, 1H), 6.16 (s, 1H), 7.24 (s, 1H); ¹³C NMR(CDCl₃) δ 20.6, 22.4, 23.6, 31.0, 43.6, 110.7, 120.9, 142.2, 148.8,170.1; MS m/z: 180 (M+H⁺). The unreacted(S)-4,5,6,7-tetrahydrobenzofuran-7-ylamine (was isolated in 39% yield(59 mg) and 94% ee (chiral GC, (S)-enantiomer_(rt)=12.6 min,(R)-enantiomer_(rt)=13.5 min); [α]_(D)=−18° (c 0.59, CHCl₃); ¹H NMR(CDCl₃, 300 MHz): δ 1.50-1.75 (m, 4H), 1.76-1.90 (m, 1H), 2.01-2.20 (m,1H), 2.30-2.50 (m, 2H), 3.94 (t, 1H, J=5.7 Hz), 6.17 (d, 1H, J=1.5 Hz),7.26 (d, 1H, J=1.5 Hz); ¹³C NMR (CDCl₃): δ 21.1, 22.6, 34.0, 45.5,110.5, 117.9, 141.3, 153.6; MS m/z: 160 (M+Na⁺).

Preparation of (R)-N-(5,6,7,8-tetrahydroquinolin-6-yl)acetamide and(S)-5,6,7,8-tetrahydroquinolin-6-ylamine

Following the general procedure, 5,6,7,8-tetrahydroquinolin-6-ylamine(251.4 mg, 1.70 mmol), CALB (75 mg), EtOAc (0.60 mL) and iPr₂O (4.8 mL)were stirred for 23 hours. The enantiomeric excess of5,6,7,8-tetrahydroquinolin-6-ylamine andN-(5,6,7,8-tetrahydroquinolin-6-yl)acetamide in a reaction mixture atthis point was 15% and 62% respectively (chiral GC method: 160° C. for10 minutes, ramp 1° C./min to 150° C., hold 50 min: (S)-2j_(rt)=81.7min, (R)-2j_(rt)=82.2 min); (S)-1j_(rt)=10.2 min, (R)-1j_(rt)=10.5 min).Further 2.0 ml of EtOAc and 75 mg of CAL were added, and the reactionmixture was stirred for 5 hours. The enantiomeric excess of(S)-5,6,7,8-tetrahydroquinolin-6-ylamine and(R)-N-(5,6,7,8-tetrahydroquinolin-6-yl)acetamide in the crude reactionmixture was 43% and 46% respectively, and the reaction was stopped.

Racemization of (R)-N-(5,6,7,8-Tetrahydroquinolin-8-yl)-acetamide and(R)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine

(R)-5,6,7,8-N-(Tetrahydroisoquinolin-8-yl)acetamide (200 mg; 98% eedetermined by chiral GC) was placed in a sealed pressure tube flushedwith argon. The reaction tube was placed in a hot (150° C.) oil bathuntil the starting material melted and heating was continued for 40minutes. The material at this point had the enantiomeric excess of 0% eeand its ¹H NMR was unchanged in comparison with the ee % of the startingmaterial. The yield of the racemized product was 200 mg (100%).

(R)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (38 g; 98% ee determined bychiral GC) was heated to 150° C. in a round bottom flask using a heatingmantle. Complete racemization was observed (chiral GC) after 30 minutesand the material turned dark in color. The reaction vessel was cooled toroom temperature. Kugelrohr distillation of the material provided theamine in 87% yield (33 g).

Racemization of (R)-5,6,7,8-N-(tetrahydroisoquinolin-5-yl)acetamide

(R)-5,6,7,8-N-(Tetrahydroisoquinolin-5-yl)acetamide (60 mg; 94% eedetermined by chiral GC) was placed in a sealed pressure tube flushedwith argon. The reaction tube was placed in a hot (150° C.) oil bathuntil the starting material melted and heating was continued for 2hours. The material at this point had the enantiomeric excess of 0% eeand its ¹H NMR was unchanged in comparison with the ee % of the startingmaterial. The yield of the racemized product was 60 mg (100%).

Asymmetric Synthesis of (R)-(−)-8-Amino-5.6,7,8-tetrahydroquinoline

Note: Depending on which chiral auxiliary is employed (i.e. either(R)-(+)- or (S)-(−)-α-methylbenzylamine, both of which are commerciallyavailable), this method can be used to generate either(R)-(−)-8-amino-5,6,7,8-tetrahydroquinoline or(S)-(+)-8-amino-5,6,7,8-tetrahydroquinoline in enantiomerically pureform. The intermediate 8-hydroxy-5,6,7,8-tetrahydroquinoline wasprepared according to the procedure described in Bridger et. al. PCTInternational application PCT/CA00/00321. For the purposes ofillustration, the synthesis of(R)-(−)-8-amino-5,6,7,8-tetrahydroquinoline is described.

Preparation of 6,7-Dihydro-5H-quinolin-8-one

To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline (13.96 g,93.6 mmol) in dry CH₂Cl₂ (400 mL) was added solid <5 micron activated85% MnO₂ (manganese IV oxide) (82.22 g, 804 mmol). The resulting blacksuspension was stirred 18 h, at which point the mixture was filteredthrough a cake of celite and washed with CH₂Cl₂ (3×50 mL). The combinedwashings were concentrated to provide 11.27 g (82%) of the titlecompound as a pale yellow solid, which was used in subsequent reactionswithout further purification. This material displayed spectra identicalto those reported above.

Preparation of(R)-(−)-(6,7-Dihydro-5H-quinolin-8-ylidene)-(1-phenylethyl)-amine

To a stirred solution of 6,7-dihydro-5H-quinolin-8-one (3.02 g, 20.5mmol) in dry MeOH (100 mL) was added (R)-(+)-α-methylbenzylamine (2.61mL, 20.5 mmol) via syringe. The resulting mixture was stirred 24 h, atwhich point additional (R)-(+)-α-methylbenzylamine (0.26 mL, 2.0 mmol)was added and the reaction was stirred for an additional 24 h. Thesolvent was removed in vacuo and dried for 3 days at room temperatureunder reduced pressure (0.1 Torr) to afford 5.38 g (95%) of the titlecompound as a red/brown solid. [α]_(D)=−126.0 (c 1.04, CHCl₃); ¹H NMR(CDCl₃) δ 1.55 (d, 3H, J=6.9 Hz), 2.17-2.29 (m, 2H), 7.35 (t, 2H, J=7.8Hz), 4.39 (q, 1H, J=6.6 Hz), 4.72 (t, 1H, J=4.7 Hz), 5.50 (br s, 11H),7.07 (dd, 1H, J=7.5, 5.1 Hz) 7.20-7.47 (m, 6H), 8.37 (d, 1H, J=2.4 Hz);³C NMR (CDCl₃) δ 21.99, 25.68, 28.29, 53.79, 98.12, 122.43, 126.33,127.03, 128.92, 132.63, 135.09, 139.47, 146.36, 150.48. ES-MS m/z 251(M+H).

Preparation of(−)-(1-(R)-1-Phenylethyl)-(8-(R)-5,6,7,8-tetrahydroquinolin-8-yl)-amine

To a cold (0° C.), stirred solution of(R)-(−)-(6,7-dihydro-5H-quinolin-8-ylidene)-(1-phenylethyl)-amine (500mg, 2.00 mmol) in dry ethanol (EtOH) (40 mL) was added solid NaBH₄(sodium borohydride) (227 mg, 6.00 mmol) in one portion. The resultingmixture was stirred 3 h at 0° C., then slowly warmed to room temperatureand stirred a further 18 h. Saturated aqueous NaHCO₃ (40 mL) was addedand the phases were separated. The aqueous layer was extracted withCH₂Cl₂ (3×50 mL) and the combined organic extracts were dried (MgSO₄)and concentrated. Flash chromatography (silica gel, 20:2:1CHCl₃—MeOH—NH₄OH) of the crude material afforded 470 mg (93%) of thetitle compound in 98% de (separated by chiral GC, J&W CycloSil B column,isothermal 180° C., (R,R)-diastereomer_(rt)=46.10 min,(S,R)-diastereomer_(rt)=46.92 min). [α]_(D)=−31.0 (c 0.65, CHCl₃); ¹HNMR (CDCl₃) δ 1.48 (d, 3H, J=7 Hz), 1.55-1.64 (m, 2H), 2.65-2.79 (m,3H), 3.86 (t, 1H, J=6 Hz), 4.10 (q, 1H, J=7 Hz), 7.05 (dd, 1H, J=8, 4Hz), 7.14-7.46 (m, 6H), 8.42 (d, 1H, J=4 Hz); ¹³C NMR (CDCl₃) δ 19.9,24.7, 30.1, 31.1, 58.3, 58.8, 77.1, 77.5, 77.9, 122.4, 127.3, 127.5,128.7, 137.4, 147.2. ES-MS m/z 253 (M+H).

Preparation of (R)-(−)-8-Amino-5,6,7,8-tetrahydroquinoline

A solution of(−)-(1-(R)-1-phenylethyl)-(8-(R)-5,6,7,8-tetrahydroquinolin-8-yl)-amine(140 mg, 0.55 mmol) and acetic acid (127 μL, 2.20 mmol) in dry MeOH (3mL) was flushed with nitrogen, then 10% palladium on carbon (32 mg) wasadded; the mixture was hydrogenated (50 psi) on a Parr Shaker for 18 h.The crude material was filtered through a cake of celite and washed withMeOH (3×10 mL) then the combined washings were concentrated. Flashchromatography (silica gel, 20:2:1 CH₂Cl₂—MeOH—NH₄OH) of the crudematerial afforded 49 mg (59%) of the title compound in 98% ee (separatedby chiral GC, J&W CycloSil B column, initial temperature: 160° C.,initial time: 0 min, rate: 1° C./min, final temperature: 130° C., finaltime: 0 min, (S)-(+)-enantiomer_(rt)=12.43 min,(R)-(−)-enantiomer_(rt)=13.13 min). [α]_(D)=−124.3 (c 0.42, CHCl₃). Thespectra of this material were identical to those reported above.

An additional example using (R)-(+)-1-phenylpropylamine as a chiralauxiliary is shown below.

Asymmetric Synthesis of (S)-(−)-8-Amino-5,6,7,8-tetrahydroquinolineUsing (S)-(−)-1-(4-Methoxyphenyl)ethylamine as Chiral Auxiliary

Preparation of(1-(S)-1-(4-Methoxyphenyl)ethyl)-(8-(S)-5,6,7,8-tetrahydroquinolin-8-yl)-amine

To a stirred solution of 6,7-dihydro-5H-quinolin-8-one (630 mg, 4.28mmol) and (S)-(−)-1-(4-methoxyphenyl)ethylamine (647 mg, 4.28 mmol) indry CH₂Cl₂ (15 mL) was added solid sodium triacetoxyborohydride (1.44 g,6.42 mmol) in one portion. The resulting mixture was stirred for 16 h.At this time, 1N aqueous NaOH (10 mL) was added to quench the reaction.The layers were separated and the aqueous phase was extracted withCH₂Cl₂ (2×10 mL). The combined organic fractions were dried (MgSO₄) andthen concentrated in vacuo. Flash chromatography (silica gel, ethylacetate) of the residue thus obtained provided 905 mg (75%) of the titlecompound as a yellowish oil. ¹H NMR (300 MHz, CDCl₃) δ 8.49 (m, 1H),7.37-7.30 (m, 3H), 7.04 (m, 1H), 6.84 (dd, J=3.3, 1.0 Hz, 1H), 4.03 (dd,J=6.6, 6.6 Hz), 3.85-3.78 (m, 4H), 2.73-2.65 (m, 3H), 1.82-1.71 (m, 2H),1.57-1.43 (m, 4H).

Preparation of (S)-(+)-8-Amino-5,6,7,8-tetrahydroquinoline

A round-bottom flask was charged with(1-(S)-1-(4-methoxyphenyl)ethyl)-(8-(S)-5,6,7,8-tetrahydroquinolin-8-yl)-amine(341 mg, 1.2 mmol) and trifluoroacetic acid (5 mL). The resultingsolution was stirred at 60° C. for 4 h. At this time, most of thetrifluoroacetic acid was removed in vacuo and the residue was taken upin CH₂Cl₂ (20 mL) and 5 N aqueous NaOH (10 mL) was added. The layerswere separated and the aqueous phase was extracted with CH₂Cl₂ (3×20mL). The combined organic layers were dried (MgSO₄) and concentrated invacuo to give 146 mg (82%) of the title compound as a yellow oil in 93%ee (separated by chiral GC, J&W CycloSil B column, initial temperature:160° C., initial time: 0 min, rate: 1° C./min, final temperature: 130°C., final time: 0 min, (S)-(+)-enantiomer_(rt)=12.43 min,(R)-(−)-enantiomer_(rt)=13.13 min. The spectra of this material wereidentical to those reported above.

Other compounds were prepared based upon the above processes and are:

N-(2-Methyl-5,6,7,8-tetrahydro-quinolin-4-yl)-acetamide

N-(1,2,3,4-Tetrahydro-quinolin-7-yl)-acetamide

N-(5,6,7,8-tetrahydroquinolin-8-yl)-acetamide

(R,S)-N-(2-Methyl-5,6,7,8-tetrahydro-quinolin-8-yl)-acetamide

1,2,3,4-Tetrahydro-quinoline-8-carboxylic acid methyl ester

(R,S)-N-(2-Methyl-1,2,3,4-tetrahydro-quinolin-8-yl)-acetamide

3-Methoxy-5,6,7,8-tetrahydro-quinoline

(R,S)-8-Amino-2-methyl-5,6,7,8-tetrahydroquinoline

(R)-N-(2-Methyl-5,6,7,8-tetrahydro-quinolin-8-yl)-acetamide

(S)-8-Amino-2-methyl-5,6,7,8-tetrahydroquinoline

(S)-5-Amino-5,6,7,8-tetrahydroquinoline

(R)-N-(5,6,7,8-tetrahydro-quinolin-5-yl)-acetamide

(S)-6-Amino-5,6,7,8-tetrahydroquinoline

(R)-N-(5,6,7,8-tetrahydro-quinolin-6-yl)-acetamide

(R,S)-5-Amino-5,6,7,8-tetrahydroisoquinoline

(S)-5-Amino-5,6,7,8-tetrahydroisoquinoline

(R)-N-(5,6,7,8-tetrahydro-isoquinolin-5-yl)-acetamide

(S)-6,7-Dihydro-5H-[1]pyrindin-7-ylamine

(R)-N-(6,7-Dihydro-5H-[1]pyrindin-7-yl)-acetamide

(S)-6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine

(R)-N-(6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-acetamide

(S)-5,6,7,8-tetrahydroquinoxalin-5-ylamine

(R)-N-(5,6,7,8-tetrahydroquinoxalin-5-yl)acetamide

(S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ylamine

(R)-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide

(S)-4,5,6,7-tetrahydrobenzofuran-7-ylamine

(R)-N-(4,5,6,7-tetrahydrobenzofuran-7-yl)acetamide

(1-(R)-1-Phenylpropyl)-(8-(R)-5,6,7,8-tetrahydroquinolin-8-yl)-amine

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons of skill in the art andare to be incorporated within the spirit and purview of this applicationand the scope of the claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference.

Citation of the above documents is not intended as an admission that anyof the foregoing is pertinent prior art, nor does it constitute anyadmission as to the contents or date of these documents.

We claim:
 1. A process for synthesizing a racemic amino-substituted5,6,7,8-tetrahydroquinoline or a racemic amino-substituted5,6,7,8-tetrahydroisoquinoline comprising: a) reacting either asubstituted 5,6,7,8-tetrahydroquinoline of the formula III or asubstituted 5,6,7,8-tetrahydroisoquinoline of the formula IV

with at least 2 equivalents of an alkyllithium base, or a lithium,sodium, or potassium amide base, and then with a nitrosating agent toform an oxime; and b) reducing the oxime to produce the racemicamino-substituted 5,6,7,8-tetrahydroquinoline or the racemicamino-substituted 5,6,7,8-tetrahydroisoquinoline; wherein the amino islocated at the 8-position on the quinoline or the 5-position on theisoquinoline; R² is located at any other hydrogen position on thequinoline or isoquinoline ring; m is 0-4; and wherein R² is selectedfrom the group consisting of halo, nitro, cyano, a protected carboxylicacid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, a protectedthiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide,an aromatic group and a heterocyclic group.
 2. The process of claim 1wherein the base is selected from the group consisting ofn-butyllithium, tert-butyllithium, lithium diisopropylamide, lithiumdicyclohexylamide, lithium 2,2,6,6-tetramethylpiperidide, potassiumhexamethyldisilazide, and any combination thereof.
 3. The process ofclaim 1 wherein the nitrosating agent is selected from the groupconsisting of alkyl nitrites and alkyl dinitrites.
 4. The process ofclaim 3 wherein the nitrosating agent is tert-butyl nitrite or isoamylnitrite.
 5. The process of claim 1 wherein from about 2 to about 3equivalents of base are utilized.
 6. The process of claim 1 wherein theoxime is reduced using zinc metal in aqueous hydrochloric acid; zincmetal in trifluoroacetic acid; hydrogen in methanol with palladium oncarbon as a catalyst; or hydrogen in methanol with Raney nickel as acatalyst.
 7. The process of claim 1 wherein m is 0 or 1; R² is methyl;and the amino is located at the 8-position on the quinoline.